2024-03-28T13:24:40Zhttps://kuscholarworks.ku.edu/oai/requestoai:kuscholarworks.ku.edu:1808/322292021-12-02T09:01:04Zcom_1808_100col_1808_101
KU ScholarWorks
author
Zhao, Yuanzi
author
Joshi, Anand A.
author
Aldrich, Jane V.
author
Murray, Thomas F.
2021-12-01T21:06:45Z
2021-12-01T21:06:45Z
2021-11
Zhao, Y., Joshi, A. A., Aldrich, J. V., & Murray, T. F. (2021). Quantification of kappa opioid receptor ligand potency, efficacy and desensitization using a real-time membrane potential assay. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 143, 112173. https://doi.org/10.1016/j.biopha.2021.112173
http://hdl.handle.net/1808/32229
10.1016/j.biopha.2021.112173
We explored the utility of the real-time FLIPR Membrane Potential (FMP) assay as a method to assess kappa opioid receptor (KOR)-induced hyperpolarization. The FMP Blue dye was used to measure fluorescent signals reflecting changes in membrane potential in KOR expressing CHO (CHO-KOR) cells. Treatment of CHO-KOR cells with kappa agonists U50,488 or dynorphin [Dyn (1−13)NH2] produced rapid and concentration-dependent decreases in FMP Blue fluorescence reflecting membrane hyperpolarization. Both the nonselective opioid antagonist naloxone and the κ-selective antagonists nor-binaltorphimine (nor-BNI) and zyklophin produced rightward shifts in the U50,488 concentration-response curves, consistent with competitive antagonism of the KOR mediated response. The decrease in fluorescent emission produced by U50,488 was blocked by overnight pertussis toxin pretreatment, indicating the requirement for PTX-sensitive G proteins in the KOR mediated response. We directly compared the potency of U50,488 and Dyn (1−13)NH2 in the FMP and [35S]GTPγS binding assays, and found that both were approximately 10 times more potent in the cellular fluorescence assay. The maximum responses of both U50,488 and Dyn (1−13)NH2 declined following repeated additions, reflecting receptor desensitization. We assessed the efficacy and potency of structurally distinct KOR small molecule and peptide ligands. The FMP assay reliably detected both partial agonists and stereoselectivity. Using KOR-selective peptides with varying efficacies, we found that the FMP assay allowed high throughput quantification of peptide efficacy. These data demonstrate that the FMP assay is a sensitive method for assessing κ-opioid receptor induced hyperpolarization, and represents a useful approach for quantification of potency, efficacy and desensitization of KOR ligands.
© 2021 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license.
Opioid
Kappa receptor
Hyperpolarization
Fluorescence
Dynorphin
Efficacy
Quantification of kappa opioid receptor ligand potency, efficacy and desensitization using a real-time membrane potential assay
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/32229/1/Zhao_2021.pdf
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oai:kuscholarworks.ku.edu:1808/245052019-04-12T14:19:40Zcom_1808_100col_1808_101
KU ScholarWorks
author
Funk, Janet L.
author
Frye, Jennifer B.
author
Oyarzo, Janice N.
author
Zhang, Huaping
author
Timmermann, Barbara N.
2017-06-14T20:56:24Z
2017-06-14T20:56:24Z
2010-01-27
Funk, J. L., Frye, J. B., Oyarzo, J. N., Zhang, H., & Timmermann, B. N. (2010). Anti-Arthritic Effects and Toxicity of the Essential Oils of Turmeric (Curcuma longa L.). Journal of Agricultural and Food Chemistry, 58(2), 842–849. http://doi.org/10.1021/jf9027206
http://hdl.handle.net/1808/24505
10.1021/jf9027206
PMC2834817
Abstract
Turmeric (Curcuma longa L., Zingiberaceae) rhizomes contain two classes of secondary metabolites, curcuminoids and the less well-studied essential oils. Having previously identified potent anti-arthritic effects of the curcuminoids in turmeric extracts in an animal model of rheumatoid arthritis (RA), studies were undertaken to determine whether the turmeric essential oils (TEO) were also joint protective using the same experimental model. Crude or refined TEO extracts dramatically inhibited joint swelling (90-100% inhibition) in female rats with streptococcal cell wall (SCW)-induced arthritis when extracts were administered via intraperitoneal injection to maximize uniform delivery. However, this anti-arthritic effect was accompanied by significant morbidity and mortality. Oral administration of a 20-fold higher dose TEO was non-toxic, but only mildly joint-protective (20% inhibition). These results do not support the isolated use of TEO for arthritis treatment, but, instead, identify potential safety concerns in vertebrates exposed to TEO.
Curcuma longa L.
Turmeric
Essential oil
Arthritis
Rheumatoid arthritis
Liver
Anemia
Anti-Arthritic Effects and Toxicity of the Essential Oils of Turmeric (Curcuma longa L.)
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/24505/1/Zhang_2010.pdf
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File
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oai:kuscholarworks.ku.edu:1808/243902019-04-12T14:18:37Zcom_1808_100col_1808_101
KU ScholarWorks
author
Clark, Daniel Forrest
author
Go, Eden P.
author
Toumi, Melinda L.
author
Desaire, Heather
2017-06-06T19:20:30Z
2017-06-06T19:20:30Z
2011-03
Clark, D. F., Go, E. P., Toumi, M. L., & Desaire, H. (2011). Collision Induced Dissociation Products of Disulfide-bonded Peptides: Ions Result from the Cleavage of More than One Bond. Journal of the American Society for Mass Spectrometry, 22(3), 492–498. http://doi.org/10.1007/s13361-010-0064-x
http://hdl.handle.net/1808/24390
10.1007/s13361-010-0064-x
PMC3543116
Disulfide bonds are a posttranslational modification (PTM) that can be scrambled or shuffled to non-native bonds during recombinant expression, sample handling, or sample purification. Currently, mapping of disulfide bonds is difficult due, to various sample requirements and data analysis difficulties. One step towards facilitating this difficult work is developing a better understanding of how disulfide-bonded peptides fragment during Collision Induced Dissociation (CID). Most automated analysis algorithms function based on the assumption that the preponderance of product ions observed during the dissociation of disulfide-bonded peptides result from the cleavage of just one peptide bond, and in this report we tested that assumption by extensively analyzing the product ions generated when several disulfide-bonded peptides are subjected to CID on a QTOF instrument. We found that one of the most common types of product ions generated resulted from two peptide bond cleavages, or a double cleavage. We found that for several of the disulfide-bonded peptides analyzed, the number of double cleavage product ions outnumbered those of single cleavages. The influence of charge state and precursor ion size was investigated, to determine if those parameters dictated the amount of double cleavage product ions formed. It was found in this sample set that no strong correlation existed between the charge state or peptide size and the portion of product ions assigned as double cleavages. This data shows that these ions could account for many of the product ions detected in CID data of disulfide bonded peptides. We also showed the utility of double cleavage product ions on a peptide with multiple cysteines present. Double cleavage products were able to fully characterize the bonding pattern of each cysteine where typical single b/y cleavage products could not.
Collision Induced Dissociation Products of Disulfide-bonded Peptides: Ions Result from the Cleavage of More than One Bond
Article
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Clark_2011.pdf.txt
oai:kuscholarworks.ku.edu:1808/265062018-07-23T16:58:25Zcom_1808_100col_1808_101
KU ScholarWorks
author
Charaschanya, Manwika
author
Aubé, Jeffrey
2018-06-13T17:53:01Z
2018-06-13T17:53:01Z
2018-03-05
Charaschanya, M., & Aubé, J. (2018). Reagent-controlled regiodivergent ring expansions of steroids. Nature Communications, 9, 934. http://doi.org/10.1038/s41467-018-03248-2
http://hdl.handle.net/1808/26506
10.1038/s41467-018-03248-2
https://orcid.org/0000-0003-1049-5767
Ring expansion provides a powerful way of introducing a heteroatom substituent into a carbocyclic framework. However, such reactions are often limited by the tendency of a given substrate to afford only one of the two rearrangement products or fail to achieve high selectivity at all. These limitations are particularly acute when seeking to carry out late-stage functionalization of natural products as starting points in drug discovery. In this work, we present a stereoelectronically controlled ring expansion sequence towards selective and flexible access to complementary ring systems derived from common steroidal substrates. Chemical diversification of the reaction intermediate affords over 100 isomerically pure analogs with spatial and functional diversity. This regiodivergent rearrangement, and the concept of using chiral reagents to affect regiocontrol in chiral natural products, should be broadly applicable to late-stage natural product diversification programs.
Copyright © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Reagent-controlled regiodivergent ring expansions of steroids
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/26506/1/Charaschanya_2018.pdf
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Charaschanya_2018.pdf.txt
oai:kuscholarworks.ku.edu:1808/236382019-04-12T14:13:37Zcom_1808_100col_1808_101
KU ScholarWorks
author
Talukdar, Arindam
author
Breen, Megan
author
Bacher, Adelbert
author
Illarionov, Boris
author
Fischer, Markus
author
Georg, Gunda I.
author
Ye, Qi-Zhuang
author
Cushman, Mark
2017-04-12T17:30:49Z
2017-04-12T17:30:49Z
2009
Talukdar, A., Breen, M., Bacher, A., Illarionov, B., Fischer, M., Georg, G., … Cushman, M. (2009). Discovery and Development of a Small Molecule Library with Lumazine Synthase Inhibitory Activity. The Journal of Organic Chemistry, 74(15), 5123–5134. http://doi.org/10.1021/jo900238q
http://hdl.handle.net/1808/23638
10.1021/jo900238q
(E)-5-Nitro-6-(2-hydroxystyryl)pyrimidine-2,4(1H,3H)-dione (9) was identified as a novel inhibitor of Schizosaccharomyces pombe lumazine synthase by high-throughput screening of a 100,000 compound library. The Ki of 9 vs. Mycobacterium tuberculosis lumazine synthase was 95 μM. Compound 9 is a structural analog of the lumazine synthase substrate, 5-amino-6-(D-ribitylamino)-2,4-(1H,3H)pyrimidinedione (1). This indicates that the ribitylamino side chain of the substrate is not essential for binding to the enzyme. Optimization of the enzyme inhibitory activity through systematic structure modification of the lead compound 9 led to (E)-5-nitro-6-(4-nitrostyryl)pyrimidine-2,4(1H,3H)-dione (26), which has a Ki of 3.7 μM vs. M. tuberculosis lumazine synthase.
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Discovery and Development of a Small Molecule Library with Lumazine Synthase Inhibitory Activity
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23638/1/Georg_2009.pdf
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oai:kuscholarworks.ku.edu:1808/233882018-10-30T17:25:41Zcom_1808_100col_1808_101
KU ScholarWorks
author
Urban, Michael Joseph
author
Pan, Pan
author
Farmer, Kevin L.
author
Zhao, Huiping
author
Blagg, Brian S. J.
author
Dobrowsky, Rick T.
2017-03-09T21:22:39Z
2017-03-09T21:22:39Z
2013-05-01
Urban, Michael J., Pan Pan, Kevin L. Farmer, Huiping Zhao, Brian S.j. Blagg, and Rick T. Dobrowsky. "Modulating Molecular Chaperones Improves Sensory Fiber Recovery and Mitochondrial Function in Diabetic Peripheral Neuropathy." Experimental Neurology 235.1 (2012): 388-96.
http://hdl.handle.net/1808/23388
10.1016/j.expneurol.2012.03.005
https://orcid.org/0000-0002-9573-9443
Quantification of intra-epidermal nerve fibers (iENFs) is an important approach to stage diabetic peripheral neuropathy (DPN) and is a promising clinical endpoint for identifying beneficial therapeutics. Mechanistically, diabetes decreases neuronal mitochondrial function and enhancing mitochondrial respiratory capacity may aid neuronal recovery from glucotoxic insults. We have proposed that modulating the activity and expression of heat shock proteins (Hsp) may be of benefit in treating DPN. KU-32 is a C-terminal Hsp90 inhibitor that improved thermal hypoalgesia in diabetic C57Bl/6 mice but it was not determined if this was associated with an increase in iENF density and mitochondrial function. After 16 weeks of diabetes, Swiss Webster mice showed decreased electrophysiological and psychosensory responses and a >30% loss of iENFs. Treatment of the mice with ten weekly doses of 20 mg/kg KU-32 significantly reversed pre-existing deficits in nerve conduction velocity and responses to mechanical and thermal stimuli. KU-32 therapy significantly reversed the pre-existing loss of iENFs despite the identification of a sub-group of drug-treated diabetic mice that showed improved thermal sensitivity but no increase in iENF density. To determine if the improved clinical indices correlated with enhanced mitochondrial activity, sensory neurons were isolated and mitochondrial bioenergetics assessed ex vivo using extracellular flux technology. Diabetes decreased maximal respiratory capacity in sensory neurons and this deficit was improved following KU-32 treatment. In conclusion, KU-32 improved physiological and morphologic markers of degenerative neuropathy and drug efficacy may be related to enhanced mitochondrial bioenergetics in sensory neurons.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Intra-epidermal nerve fibers
Sensory neurons
Nerve conduction velocity
Mitochondria
Bioenergetics
Respiratory capacity
Modulating molecular chaperones improves sensory fiber recovery and mitochondrial function in diabetic peripheral neuropathy
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23388/1/blagg_modulating.pdf
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blagg_modulating.pdf.txt
oai:kuscholarworks.ku.edu:1808/327542022-05-05T08:01:02Zcom_1808_100col_1808_101
KU ScholarWorks
author
Nagamalla, Someshwar
author
Mague, Joel T.
author
Sathyamoorthi, Shyam
2022-05-04T15:37:43Z
2022-05-04T15:37:43Z
2022-01-18
Nagamalla, S., Mague, J. T., & Sathyamoorthi, S. (2022). Ring Opening of Epoxides by Pendant Silanols. Organic letters, 24(3), 939–943. https://doi.org/10.1021/acs.orglett.1c04310
http://hdl.handle.net/1808/32754
10.1021/acs.orglett.1c04310
PMC8965746
We present a new ring-opening reaction of epoxides by pendant silanols, catalyzed by either Ph3C+BF4– or BINOL-phosphoric acid. Silanol epoxides derived from trans-allylic alcohols, cis-allylic alcohols, trans-homoallylic alcohols, and cis-homoallylic alcohols were all compatible and gave products from either endo- or exo-ring opening. With silanol epoxides derived from 4-alkenyl silanols, an unusual rearrangement to tetrahydrofuran products was observed. The utility of this methodology was demonstrated in a short preparation of protected d-arabitol.
Copyright © 2022 American Chemical Society.
Ring Opening of Epoxides by Pendant Silanols
Article
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URL
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oai:kuscholarworks.ku.edu:1808/297322020-07-24T14:06:37Zcom_1808_100col_1808_101
KU ScholarWorks
author
Wolfe, Michael S.
2019-11-07T22:08:03Z
2019-11-07T22:08:03Z
2019-06-14
Wolfe M. S. (2019). Structure and Function of the γ-Secretase Complex. Biochemistry, 58(27), 2953–2966. doi:10.1021/acs.biochem.9b00401
http://hdl.handle.net/1808/29732
10.1021/acs.biochem.9b00401
https://orcid.org/0000-0002-5721-9092
PMC6618299
γ-Secretase is a membrane-embedded protease complex, with presenilin as the catalytic component containing two transmembrane aspartates in the active site. With more than 90 known substrates, the γ-secretase complex is considered “the proteasome of the membrane”, with central roles in biology and medicine. The protease carries out hydrolysis within the lipid bilayer to cleave the transmembrane domain of the substrate multiple times before releasing secreted products. For many years, elucidation of γ-secretase structure and function largely relied on small-molecule probes and mutagenesis. Recently, however, advances in cryo-electron microscopy have led to the first detailed structures of the protease complex. Two new reports of structures of γ-secretase bound to membrane protein substrates provide great insight into the nature of substrate recognition and how Alzheimer’s disease-causing mutations in presenilin might alter substrate binding and processing. These new structures offer a powerful platform for elucidating enzyme mechanisms, deciphering effects of disease-causing mutations, and advancing Alzheimer’s disease drug discovery.
Copyright © 2019 American Chemical Society
Structure and Function of the γ-Secretase Complex
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/29732/1/Wolfe_2019.pdf
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oai:kuscholarworks.ku.edu:1808/232212019-04-12T14:22:14Zcom_1808_100col_1808_101
KU ScholarWorks
author
Hymel, David
author
Cai, Sutang
author
Henkhaus, Rebecca S.
author
Perera, Chamani
author
Peterson, Blake R.
2017-02-22T20:46:12Z
2017-02-22T20:46:12Z
2016-10-07
Hymel, David, Sutang Cai, Qi Sun, Rebecca S. Henkhaus, Chamani Perera, and Blake R. Peterson. "Fluorescent Mimics of Cholesterol That Rapidly Bind Surfaces of Living Mammalian Cells." Chem. Commun. 51.78 (2015): 14624-4627.
http://hdl.handle.net/1808/23221
10.1039/c5cc06325f
Mammalian cells acquire cholesterol, a critical membrane constituent, through multiple mechanisms. We synthesized mimics of cholesterol, fluorescent N-alkyl-3β-cholesterylamine-glutamic acids, that are rapidly incorporated into cellular plasma membranes compared with analogous cholesteryl amides, ethers, esters, carbamates, and a sitosterol analogue. This process was inhibited by ezetimibe, indicating a receptor-mediated uptake pathway.
Fluorescent Mimics of Cholesterol that Rapidly Bind Surfaces of Living Mammalian Cells
Article
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oai:kuscholarworks.ku.edu:1808/231822018-07-23T16:53:25Zcom_1808_100col_1808_101
KU ScholarWorks
author
Zhou, Lei
author
Stahl, Edward L.
author
Lovell, Kimberly M.
author
Frankowski, Kevin J.
author
Prisinzano, Thomas E.
author
Aubé, Jeffrey
author
Bohn, Laura M.
2017-02-15T19:32:21Z
2017-02-15T19:32:21Z
2015-12
Zhou, L., Stahl, E. L., Lovell, K. M., Frankowski, K. J., Prisinzano, T. E., Aubé, J., & Bohn, L. M. (2015). Characterization of kappa opioid receptor mediated, dynorphin-stimulated [35S]GTPγS binding in mouse striatum for the evaluation of selective KOR ligands in an endogenous setting. Neuropharmacology, 99, 131–141. http://doi.org/10.1016/j.neuropharm.2015.07.001
http://hdl.handle.net/1808/23182
10.1016/j.neuropharm.2015.07.001
https://orcid.org/0000-0003-1049-5767
Differential modulation of kappa opioid receptor (KOR) signaling has been a proposed strategy for developing therapies for drug addiction and depression by either activating or blocking this receptor. Hence, there have been significant efforts to generate ligands with diverse pharmacological properties including partial agonists, antagonists, allosteric modulators as well as ligands that selectively activate some pathways while not engaging others (biased agonists). It is becoming increasingly evident that G protein coupled receptor signaling events are context dependent and that what may occur in cell based assays may not be fully indicative of signaling events that occur in the naturally occurring environment. As new ligands are developed, it is important to assess their signaling capacity in relevant endogenous systems in comparison to the performance of endogenous agonists. Since KOR is considered the cognate receptor for dynorphin peptides we have evaluated the selectivity profiles of dynorphin peptides in wild-type (WT), KOR knockout (KOR-KO), and mu opioid receptor knockout (MOR-KO) mice using [35S]GTPγS binding assay in striatal membrane preparations. We find that while the small molecule KOR agonist U69,593, is very selective for KOR, dynorphin peptides promiscuously stimulate G protein signaling in striatum. Furthermore, our studies demonstrate that norBNI and 5′GNTI are highly nonselective antagonists as they maintain full potency and efficacy against dynorphin signaling in the absence of KOR. Characterization of a new KOR antagonist, which may be more selective than NorBNI and 5′GNTI, is presented using this approach.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Dynorphin
Kappa opioid receptor
[35S]GTPγS binding
Mouse striatum
Selectivity
Drug discovery
KOR antagonist
Characterization of kappa opioid receptor mediated, dynorphin-stimulated [35S]GTPγS binding in mouse striatum for the evaluation of selective KOR ligands in an endogenous setting
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23182/1/Frankowski_2015.pdf
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oai:kuscholarworks.ku.edu:1808/176522019-04-12T14:16:06Zcom_1808_100col_1808_101
KU ScholarWorks
author
Graci, Jason D.
author
Too, Kathleen
author
Smidansky, Eric D.
author
Edathil, Jocelyn P.
author
Barr, Eric W.
author
Harki, Daniel A.
author
Gakarraga, Jessica E.
author
Bollinger, J. Martin Jr.
author
Peterson, Blake R.
author
Loakes, David
author
Brown, Daniel M.
author
Cameron, Craig E.
2015-05-07T20:54:31Z
2015-05-07T20:54:31Z
2008-03
Graci et al. "Lethal Mutagenesis of Picornaviruses with N-6-Modified Purine Nucleoside Analogues." Antimicrob. Agents Chemother. March 2008 vol. 52 no. 3 971-979.
http://dx.doi.org/10.1128/AAC.01056-07
http://hdl.handle.net/1808/17652
10.1128/AAC.01056-07
RNA viruses exhibit extraordinarily high mutation rates during genome replication. Nonnatural ribonucleosides that can increase the mutation rate of RNA viruses by acting as ambiguous substrates during replication have been explored as antiviral agents acting through lethal mutagenesis. We have synthesized novel N-6-substituted purine analogues with ambiguous incorporation characteristics due to tautomerization of the nucleobase. The most potent of these analogues reduced the titer of poliovirus (PV) and coxsackievirus (CVB3) over 1,000-fold during a single passage in HeLa cell culture, with an increase in transition mutation frequency up to 65-fold. Kinetic analysis of incorporation by the PV polymerase indicated that these analogues were templated ambiguously with increased efficiency compared to the known mutagenic nucleoside ribavirin. Notably, these nucleosides were not efficient substrates for cellular ribonucleotide reductase in vitro, suggesting that conversion to the deoxyriboucleoside may be hindered, potentially limiting genetic damage to the host cell. Furthermore, a high-fidelity PV variant (G64S) displayed resistance to the antiviral effect and mutagenic potential of these analogues. These purine nucleoside analogues represent promising lead compounds in the development of clinically useful antiviral therapies based on the strategy of lethal mutagenesis.
Lethal Mutagenesis of Picornaviruses with N-6-Modified Purine Nucleoside Analogues
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/17652/1/PetersonB_AAC_52%283%29971.pdf
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URL
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oai:kuscholarworks.ku.edu:1808/83182019-04-12T14:44:58Zcom_1808_8219com_1808_100col_1808_8220col_1808_101
KU ScholarWorks
author
Anderson, R. J.
author
Hanzlik, Robert P.
author
Sharpless, K. B.
author
van Tamelen, E. E.
author
Clayton, R. B.
2011-10-31T16:26:53Z
2011-10-31T16:26:53Z
1969
R. J. Anderson, R. P. Hanzlik, K. B. Sharpless, E. E. van Tamelen, and R. B. Clayton, "Enzymic Transformation of an Acyclic Sesterterpene Terminal Epoxide to a Lanosterol Analog," Chemical Communications, 53 (1969). http://dx.doi.org/10.1039/C29690000053
http://hdl.handle.net/1808/8318
10.1039/C29690000053
en
Enzymic transformation of an acyclic sesterterpene terminal epoxide into a lanosterol analogue
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/8318/1/c29690000053.pdf
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oai:kuscholarworks.ku.edu:1808/235222019-04-12T14:25:09Zcom_1808_100col_1808_101
KU ScholarWorks
author
Duerfeldt, Adam S.
author
Blagg, Brian S. J.
2017-03-30T17:57:57Z
2017-03-30T17:57:57Z
2009-04-17
Duerfeldt, A. S., & Blagg, B. S. J. (2009). Hydrating for Resistance to Radicicol. ACS Chemical Biology, 4(4), 245–247. http://doi.org/10.1021/cb9000712
http://hdl.handle.net/1808/23522
10.1021/cb9000712
https://orcid.org/0000-0002-3130-9890
Resistance to Hsp90 inhibition has become an important concern as several clinical trials are currently
in progress for the treatment of cancer. A summary of known mechanisms of resistance to Hsp90
inhibitors is provided, including the recent solution of the Humicola fuscoatra Hsp90 structure, the
organism responsible for the biosynthesis of radicicol. Through careful analyses of Hsp90 structures,
a plausible mechanism for resistance to Hsp90 inhibitors has been obtained by single mutations about
the N-terminal ATP-binding site.
© 2009 American Chemical Society
Hydrating for Resistance to Radicicol
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23522/1/Duerfeldt_ACSChemBiol_2009.pdf
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Duerfeldt_ACSChemBiol_2009.pdf.txt
oai:kuscholarworks.ku.edu:1808/200452019-04-12T14:40:11Zcom_1808_100col_1808_101
KU ScholarWorks
author
Matts, Robert L.
author
Brandt, Gary E. L.
author
Lu, Yuanming
author
Dixit, Anshuman
author
Mollapour, Mehdi
author
Wang, Suiquan
author
Donnelly, Alison C.
author
Neckers, Leonard
author
Verkhivker, Gennady M.
author
Blagg, Brian S. J.
2016-02-12T21:38:09Z
2016-02-12T21:38:09Z
2010-10-19
Matts, Robert L., Gary E.l. Brandt, Yuanming Lu, Anshuman Dixit, Mehdi Mollapour, Suiquan Wang, Alison C. Donnelly, Leonard Neckers, Gennady Verkhivker, and Brian S.j. Blagg. "A Systematic Protocol for the Characterization of Hsp90 Modulators." Bioorganic & Medicinal Chemistry 19.1 (2011): 684-92. doi:10.1016/j.bmc.2010.10.029.
http://hdl.handle.net/1808/20045
10.1016/j.bmc.2010.10.029
Several Hsp90 modulators have been identified including the N-terminal ligand geldanamycin (GDA), the C-terminal ligand novobiocin (NB), and the co-chaperone disruptor celastrol. Other Hsp90 modulators elicit a mechanism of action that remains unknown. For example, the natural product gedunin and the synthetic anti-spermatogenic agent H2-gamendazole, recently identified Hsp90 modulators, manifest biological activity through undefined mechanisms. Herein, we report a series of biochemical techniques used to classify such modulators into identifiable categories. Such studies provided evidence that gedunin and H2-gamendazole both modulate Hsp90 via a mechanism similar to celastrol, and unlike NB or GDA.
Heat shock protein 90
Novobiocin
Geldanamycin
Celastrol
Gedunin
A Systematic Protocol for the Characterization of Hsp90 Modulators
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/20045/1/blagg_systematic.pdf
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blagg_systematic.pdf.txt
oai:kuscholarworks.ku.edu:1808/263712018-11-01T16:50:30Zcom_1808_100col_1808_101
KU ScholarWorks
author
Chun, Lani S.
author
Vekariya, Rakesh H.
author
Free, R. Benjamin
author
Li, Yun
author
Lin, Da-Ting
author
Su, Ping
author
Liu, Fang
author
Namkung, Yoon
author
Laporte, Stephane A.
author
Moritz, Amy E.
author
Aubé, Jeffrey
author
Frankowski, Kevin J.
author
Sibley, David R.
2018-04-26T17:23:08Z
2018-04-26T17:23:08Z
2018-02-21
Chun, L. S., Vekariya, R. H., Free, R. B., Li, Y., Lin, D.-T., Su, P., … Sibley, D. R. (2018). Structure-Activity Investigation of a G Protein-Biased Agonist Reveals Molecular Determinants for Biased Signaling of the D2 Dopamine Receptor. Frontiers in Synaptic Neuroscience, 10, 2. http://doi.org/10.3389/fnsyn.2018.00002
http://hdl.handle.net/1808/26371
10.3389/fnsyn.2018.00002
https://orcid.org/0000-0003-1049-5767
https://orcid.org/0000-0001-8292-9793
The dopamine D2 receptor (D2R) is known to elicit effects through activating two major signaling pathways mediated by either G proteins (Gi/o) or β-arrestins. However, the specific role of each pathway in physiological or therapeutic activities is not known with certainty. One approach to the dissection of these pathways is through the use of drugs that can selectively modulate one pathway vs. the other through a mechanism known as functional selectivity or biased signaling. Our laboratory has previously described a G protein signaling-biased agonist, MLS1547, for the D2R using a variety of in vitro functional assays. To further evaluate the biased signaling activity of this compound, we investigated its ability to promote D2R internalization, a process known to be mediated by β-arrestin. Using multiple cellular systems and techniques, we found that MLS1547 promotes little D2R internalization, which is consistent with its inability to recruit β-arrestin. Importantly, we validated these results in primary striatal neurons where the D2R is most highly expressed suggesting that MLS1547 will exhibit biased signaling activity in vivo. In an effort to optimize and further explore structure-activity relationships (SAR) for this scaffold, we conducted an iterative chemistry campaign to synthesize and characterize novel analogs of MLS1547. The resulting analysis confirmed previously described SAR requirements for G protein-biased agonist activity and, importantly, elucidated new structural features that are critical for agonist efficacy and signaling bias of the MLS1547 scaffold. One of the most important determinants for G protein-biased signaling is the interaction of a hydrophobic moiety of the compound with a defined pocket formed by residues within transmembrane five and extracellular loop two of the D2R. These results shed new light on the mechanism of biased signaling of the D2R and may lead to improved functionally-selective molecules.
Copyright © 2018 Chun, Vekariya, Free, Li, Lin, Su, Liu, Namkung, Laporte, Moritz, Aubé, Frankowski and Sibley. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
D2 dopamine receptor
Functional selectivity
Biased signaling
Structure-activity relationship
MLS1547
Quinoline
Structure-Activity Investigation of a G Protein-Biased Agonist Reveals Molecular Determinants for Biased Signaling of the D2 Dopamine Receptor
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/26371/1/Vekariya_2018.pdf
File
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URL
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oai:kuscholarworks.ku.edu:1808/235892019-04-12T14:12:57Zcom_1808_100col_1808_101
KU ScholarWorks
author
Sinha, Bhaswati
author
Cao, Zhengyu
author
Murray, Thomas F.
author
Aldrich, Jane V.
2017-04-06T16:45:34Z
2017-04-06T16:45:34Z
2009-12-10
Sinha, B., Cao, Z., Murray, T. F., & Aldrich, J. V. (2009). Discovery of Dermorphin-Based Affinity Labels with Subnanomolar Affinity for Mu Opioid Receptors. Journal of Medicinal Chemistry, 52(23), 7372–7375. http://doi.org/10.1021/jm9007592
http://hdl.handle.net/1808/23589
10.1021/jm9007592
A series of potent electrophilic affinity labels (IC50 = 0.1-5 nM) containing either a bromoacetamide or isothiocyanate based on the mu opioid receptor (MOR) selective peptide dermorphin were prepared. All four analogs exhibited wash resistant inhibition of [3H]DAMGO binding at subnanomolar to nanomolar concentrations, suggesting that these analogs bind covalently to MOR. To our knowledge these peptides are the highest affinity peptide-based affinity labels for MOR reported to date.
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm9007592.
Discovery of Dermorphin-Based Affinity Labels with Subnanomolar Affinity for Mu Opioid Receptors+
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23589/1/Sinha_2009.pdf
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oai:kuscholarworks.ku.edu:1808/132802018-10-31T16:31:53Zcom_1808_100col_1808_101
KU ScholarWorks
author
Shukla, Nikunj M.
author
Salunke, Deepak B.
author
Balakrishna, Rajalakshmi
author
Mutz, Cole A.
author
Malladi, Subbalakshmi S.
author
David, Sunil A.
2014-03-19T21:41:21Z
2014-03-19T21:41:21Z
2012-08-28
Shukla, N. M., Salunke, D. B., Balakrishna, R., Mutz, C. A., Malladi, S. S., & David, S. A. (2012). Potent Adjuvanticity of a Pure TLR7-Agonistic Imidazoquinoline Dendrimer. PLoS ONE, 7(8). http://dx.doi.org/10.1371/journal.pone.0043612
http://hdl.handle.net/1808/13280
10.1371/journal.pone.0043612
https://orcid.org/0000-0002-1241-9146
Engagement of toll-like receptors (TLRs) serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary and anamnestic immune responses. TLR7 agonists are highly immunostimulatory without inducing dominant proinflammatory cytokine responses. We synthesized a dendrimeric molecule bearing six units of a potent TLR7/TLR8 dual-agonistic imidazoquinoline to explore if multimerization of TLR7/8 would result in altered activity profiles. A complete loss of TLR8-stimulatory activity with selective retention of the TLR7-agonistic activity was observed in the dendrimer. This was reflected by a complete absence of TLR8-driven proinflammatory cytokine and interferon (IFN)-γ induction in human PBMCs, with preservation of TLR7-driven IFN-α induction. The dendrimer was found to be superior to the imidazoquinoline monomer in inducing high titers of high-affinity antibodies to bovine α-lactalbumin. Additionally, epitope mapping experiments showed that the dendrimer induced immunoreactivity to more contiguous peptide epitopes along the amino acid sequence of the model antigen.
© Shukla et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Anitbodies
Bovines
Cytokines
Enzyme-linked immunoassays
Epitope mapping
Immune response
Peptide mapping
Protein sequencing
Potent Adjuvanticity of a Pure TLR7-Agonistic Imidazoquinoline Dendrimer
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/13280/1/Shukla.pdf
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oai:kuscholarworks.ku.edu:1808/240822018-12-05T16:57:09Zcom_1808_100col_1808_101
KU ScholarWorks
author
Kusuma, Bhaskar Reddy
author
Khandelwal, Anuj
author
Gu, Wen
author
Brown, Douglas
author
Liu, Weiya
author
Vielhauer, George A.
author
Holzbeierlein, Jeffery M.
author
Blagg, Brian S. J.
2017-05-10T18:40:01Z
2017-05-10T18:40:01Z
2014-02-15
Kusuma, B. R., Khandelwal, A., Gu, W., Brown, D., Liu, W., Vielhauer, G., … Blagg, B. S. J. (2014). Synthesis and Biological Evaluation of Coumarin Replacements of Novobiocin as Hsp90 Inhibitors. Bioorganic & Medicinal Chemistry, 22(4), 1441–1449. http://doi.org/10.1016/j.bmc.2013.12.056
http://hdl.handle.net/1808/24082
10.1016/j.bmc.2013.12.056
https://orcid.org/0000-0003-4492-4400
PMC3963410
Since Hsp90 modulates all six hallmarks of cancer simultaneously, it has become an attractive target for the development of cancer chemotherapeutics. In an effort to develop more efficacious compounds for Hsp90 inhibition, novobiocin analogues were prepared by replacing the central coumarin core with naphthalene, quinolinone, and quinoline surrogates. These modifications allowed for modification of the 2-position, which was previously unexplored. Biological evaluation of these compounds suggests a hydrophobic pocket about the 2-position of novobiocin. Anti-proliferative activities of these analogues against multiple cancer cell lines identified 2-alkoxyquinoline derivatives to exhibit improved activity.
This article is made available under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported (CC BY-NC-ND 3.0)
License.
Synthesis and Biological Evaluation of Coumarin Replacements of Novobiocin as Hsp90 Inhibitors
Article
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URL
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oai:kuscholarworks.ku.edu:1808/236412019-04-12T14:13:24Zcom_1808_100col_1808_101
KU ScholarWorks
author
Huh, Chan Woo
author
Somal, Gagandeep K.
author
Katz, Christopher E.
author
Pei, Huanxing
author
Zeng, Yibin
author
Douglas, Justin T.
author
Aubé, Jeffrey
2017-04-12T18:13:44Z
2017-04-12T18:13:44Z
2009-10-16
Huh, C. W., Somal, G. K., Katz, C. E., Pei, H., Zeng, Y., Douglas, J. T., & Aubé, J. (2009). One-pot Synthesis of Lactams Using Domino Reactions: Combination of Schmidt Reaction with Sakurai and Aldol Reactions. The Journal of Organic Chemistry, 74(20), 7618–7626. http://doi.org/10.1021/jo901843w
http://hdl.handle.net/1808/23641
10.1021/jo901843w
https://orcid.org/0000-0003-1049-5767
A series of domino reactions in which the intramolecular Schmidt reaction is combined with either a Sakurai reaction, an aldol reaction, or both is reported. The Sakurai reaction of an allylsilane with an azido-containing enone under Lewis acidic conditions followed by protonation of the resulting titanium enolate species allowed for a subsequent intramolecular Schmidt reaction. Alternatively, the intermediate titanium enolate could undergo an aldol reaction, followed by the intramolecular Schmidt reaction to form lactam products with multiple stereogenic centers. The stereochemical features of the titanium enolate aldol reaction with several 3-azidoaldehyde substrates during this domino process is discussed.
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Organic Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jo901843w.
Schmidt reaction
Lactam synthesis
Azides
Domino reaction
Sakurai reaction
Stereoselective aldol reaction
Titanium enolate
GOESY
One-pot Synthesis of Lactams Using Domino Reactions: Combination of Schmidt Reaction with Sakuri and Aldol Reaction
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23641/1/Aub%c3%a9_2009.pdf
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oai:kuscholarworks.ku.edu:1808/238962018-11-28T17:46:39Zcom_1808_100col_1808_101
KU ScholarWorks
author
Shukla, Nikunj M.
author
Malladi, Subbalakshmi S.
author
Day, Victor W.
author
David, Sunil A.
2017-05-04T19:20:48Z
2017-05-04T19:20:48Z
2011-06-15
Shukla, N. M., Malladi, S. S., Day, V., & David, S. A. (2011). Preliminary Evaluation of a 3H Imidazoquinoline Library as Dual TLR7/TLR8 Antagonists. Bioorganic & Medicinal Chemistry, 19(12), 3801–3811. http://doi.org/10.1016/j.bmc.2011.04.052
http://hdl.handle.net/1808/23896
10.1016/j.bmc.2011.04.052
PMC3114175
Toll-like receptors (TLR) -7 and -8 are thought to play an important role in immune activation processes underlying the pathophysiology of HIV and several clinically important autoimmune diseases. Based on our earlier findings of TLR7-antagonistic activity in a 3H imidazoquinoline, we sought to examine a pilot library of 3H imidazoquinolines for dual TLR7/8 antagonists, since they remain a poorly explored chemotype. Two-dimensional NOE experiments were employed to unequivocally characterize the compounds. A quinolinium compound 12, bearing p-methoxybenzyl substituents on N3 and N5 positions was identified as a lead. Compound 12 was found to inhibit both TLR7 and TLR8 at low micromolar concentrations. Our preliminary results suggest that alkylation with electron-rich substituents on the quinoline N5, or conversely, elimination of the fixed charge of the resultant quaternary amine on the quinolinium may yield more active compounds.
This article is made available under an Attribution-NonCommercial-NoDerivs 3.0 United States (CC BY-NC-ND 3.0 US) License.
Toll-like receptor
TLR7
TLR8
Imidazoquinoline
NOESY
HIV
Autoimmune diseases
Preliminary Evaluation of a 3H Imidazoquinoline Library as Dual TLR7/TLR8 Antagonists
Article
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https://kuscholarworks.ku.edu/bitstream/1808/23896/1/Shukla_Elsevier_2011.pdf
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oai:kuscholarworks.ku.edu:1808/343742023-06-14T06:05:42Zcom_1808_100col_1808_101
KU ScholarWorks
author
Paul, Debobrata
author
Mague, Joel T.
author
Sathyamoorthi, Shyam
2023-06-13T20:45:14Z
2023-06-13T20:45:14Z
2023-01-17
Paul, D., Mague, J. T., & Sathyamoorthi, S. (2023). Sulfamate-Tethered Aza-Wacker Cyclization Strategy for the Syntheses of 2-Amino-2-deoxyhexoses: Preparation of Orthogonally Protected d-Galactosamines. The Journal of organic chemistry, 88(3), 1445–1456. https://doi.org/10.1021/acs.joc.2c02346
https://hdl.handle.net/1808/34374
10.1021/acs.joc.2c02346
https://orcid.org/0000-0002-5270-7177https://orcid.org/0000-0003-4705-7349
PMC10019460
We present a new strategy for the assembly of protected d-galactosamine synthons. Our route uses a sulfamate-tethered aza-Wacker cyclization as a key step and commences from d-erythrono-1,4-lactone. This stands in contrast to most literature syntheses of 2-amino-2-deoxyhexose derivatives, as these generally employ glycals or hexoses as starting materials. This strategy may serve as a template for the assembly of many other 2-amino-2-deoxyhexoses with protection patterns difficult to access by conventional methods.
Copyright © 2023 American Chemical Society
Cyclization
Layers
Lipids
Mixtures
Silica
Sulfamate-Tethered Aza-Wacker Cyclization Strategy for the Syntheses of 2-Amino-2-deoxyhexoses: Preparation of Orthogonally Protected d-Galactosamines
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/34374/1/Paul_2023.pdf
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oai:kuscholarworks.ku.edu:1808/133902018-07-13T15:18:29Zcom_1808_8219com_1808_100col_1808_8220col_1808_101
KU ScholarWorks
author
Choi, Seungbum
author
Aljakna, Alesksandra
author
Srivastava, Ujala
author
Peterson, Blake R.
author
Deng, Bin
author
Prat, Annik
author
Korstanje, Ron
2014-04-01T14:25:55Z
2014-04-01T14:25:55Z
2013-07-24
Choi, Seungbum, Aleksandra Aljakna, Ujala Srivastava, Blake R Peterson, Bin Deng, Annik Prat, and Ron Korstanje. 2013. “Decreased APOE-Containing HDL Subfractions and Cholesterol Efflux Capacity of Serum in Mice Lacking Pcsk9.” Lipids in Health and Disease 12:112. http://dx.doi.org/10.1186/1476-511X-12-112.
http://hdl.handle.net/1808/13390
10.1186/1476-511X-12-112
Background
Studies in animals showed that PCSK9 is involved in HDL metabolism. We investigated the molecular mechanism by which PCSK9 regulates HDL cholesterol concentration and also whether Pcsk9 inactivation might affect cholesterol efflux capacity of serum and atherosclerotic fatty streak volume.
Methods
Mass spectrometry and western blot were used to analyze the level of apolipoprotein E (APOE) and A1 (APOA1). A mouse model overexpressing human LDLR was used to test the effect of high levels of liver LDLR on the concentration of HDL cholesterol and APOE-containing HDL subfractions. Pcsk9 knockout males lacking LDLR and APOE were used to test whether LDLR and APOE are necessary for PCSK9-mediated HDL cholesterol regulation. We also investigated the effects of Pcsk9 inactivation on cholesterol efflux capacity of serum using THP-1 and J774.A1 macrophage foam cells and atherosclerotic fatty streak volume in the aortic sinus of Pcsk9 knockout males fed an atherogenic diet.
Results
APOE and APOA1 were reduced in the same HDL subfractions of Pcsk9 knockout and human LDLR transgenic male mice. In Pcsk9/Ldlr double-knockout mice, HDL cholesterol concentration was lower than in Ldlr knockout mice and higher than in wild-type controls. In Pcsk9/Apoe double-knockout mice, HDL cholesterol concentration was similar to that of Apoe knockout males. In Pcsk9 knockout males, THP-1 macrophage cholesterol efflux capacity of serum was reduced and the fatty streak lesion volume was similar to wild-type controls.
Conclusions
In mice, LDLR and APOE are important factors for PCSK9-mediated HDL regulation. Our data suggest that, although LDLR plays a major role in PCSK9-mediated regulation of HDL cholesterol concentration, it is not the only mechanism and that, regardless of mechanism, APOE is essential. Pcsk9 inactivation decreases the HDL cholesterol concentration and cholesterol efflux capacity in serum, but does not increase atherosclerotic fatty streak volume.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Apolipoprotein e
Atherosclerotic fatty streak
Low-density lipoprotein receptor
Macrophage foam cell
Proprotein convertase subtilisin/kexin type 9
Decreased APOE-containing HDL subfractions and cholesterol efflux capacity of serum in mice lacking Pcsk9.
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/13390/1/Choi_2013.pdf
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oai:kuscholarworks.ku.edu:1808/225722019-04-12T14:17:23Zcom_1808_100col_1808_101
KU ScholarWorks
author
Woydziak, Zachary R.
author
Fu, Liqiang
author
Peterson, Blake R.
2017-01-11T19:46:32Z
2017-01-11T19:46:32Z
2015-01-01
Peterson, Blake, Zachary Woydziak, and Liqiang Fu. "Efficient and Scalable Synthesis of 4-Carboxy-Pennsylvania Green Methyl Ester: A Hydrophobic Building Block for Fluorescent Molecular Probes." Synthesis 46.02 (2013): 158-64.
http://hdl.handle.net/1808/22572
10.1055/s-0033-1338535
Fluorinated fluorophores are valuable tools for studies of biological systems. However, amine-reactive single-isomer derivatives of these compounds are often very expensive. To provide an inexpensive alternative, we report a practical synthesis of 4-carboxy-Pennsylvania Green methyl ester. Derivatives of this hydrophobic fluorinated fluorophore, a hybrid of the dyes Oregon Green and Tokyo Green, are often cell permeable, enabling labeling of intracellular targets and components. Moreover, the low pKa of Pennsylvania Green (4.8) confers bright fluorescence in acidic cellular compartments such as endosomes, enhancing its utility for chemical biology investigations. To improve access to the key intermediate 2,7-difluoro-3,6-dihydroxyxanthen-9-one, we subjected bis-(2,4,5-trifluorophenyl)methanone to iterative nucleophilic aromatic substitution by hydroxide on scales of > 40 g. This intermediate was used to prepare over 15 grams of pure 4-carboxy-Pennsylvania Green methyl ester in 28% overall yield without requiring chromatography. This compound can be converted into the amine reactive N-hydroxysuccinimidyl ester in essentially quantitative yield for the synthesis of a wide variety of fluorescent molecular probes.
Fluorophore
Bioorganic chemistry
Chemical biology
Molecular probes
Fluorine
Conjugation
Efficient and Scalable Synthesis of 4-Carboxy-Pennsylvania Green Methyl Ester: A Hydrophobic Building Block for Fluorescent Molecular Probes
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/22572/1/peterson_efficient.pdf
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oai:kuscholarworks.ku.edu:1808/249652019-04-12T14:20:25Zcom_1808_100col_1808_101
KU ScholarWorks
author
Qian, Pengxu
author
He, Xi C.
author
Paulson, Ariel
author
Li, Zhenrui
author
Tao, Fang
author
Perry, John M.
author
Guo, Fengli
author
Zhao, Meng
author
Zhi, Lei
author
Venkatraman, Aparna
author
Haug, Jeffrey S.
author
Parmely, Tari
author
Li, Hua
author
Dobrowsky, Rick T.
author
Ding, Weng-Xing
author
Kono, Tomohiro
author
Ferguson-Smith, Anne C.
author
Li, Linheng
2017-09-15T16:23:34Z
2017-09-15T16:23:34Z
2016-02
Qian, P., He, X. C., Paulson, A., Li, Z., Tao, F., Perry, J. M., … Li, L. (2016). The Dlk1-Gtl2 Locus Preserves LT-HSC Function by Inhibiting the PI3K-mTOR Pathway to Restrict Mitochondrial Metabolism. Cell Stem Cell, 18(2), 214–228. http://doi.org/10.1016/j.stem.2015.11.001
http://hdl.handle.net/1808/24965
10.1016/j.stem.2015.11.001
PMC5545934
The mammalian imprinted Dlk1-Gtl2 locus produces multiple non-coding RNAs (ncRNAs) from the maternally inherited allele, including the largest miRNA cluster in the mammalian genome. This locus has characterized functions in some types of stem cell, but its role in hematopoietic stem cells (HSCs) is unknown. Here, we show that the Dlk1-Gtl2 locus plays a critical role in preserving long-term repopulating HSCs (LT-HSCs). Through transcriptome profiling in 17 hematopoietic cell types, we found that ncRNAs expressed from the Dlk1-Gtl2 locus are predominantly enriched in fetal liver HSCs and the adult LT-HSC population and sustain long-term HSC functionality. Mechanistically, the miRNA mega-cluster within the Dlk1-Gtl2 locus suppresses the entire PI3K-mTOR pathway. This regulation in turn inhibits mitochondrial biogenesis and metabolic activity and protects LT-HSCs from excessive reactive oxygen species (ROS) production. Our data therefore show that the imprinted Dlk1-Gtl2 locus preserves LT-HSC function by restricting mitochondrial metabolism.
Copyright © 2016 Elsevier Inc. All rights reserved.
The Dlk1-Gtl2 Locus Preserves LT-HSC Function by Inhibiting the PI3K-mTOR Pathway to Restrict Mitochondrial Metabolism
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/24965/1/Qian_CellStemCell_2016.pdf
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oai:kuscholarworks.ku.edu:1808/236312019-04-12T14:13:34Zcom_1808_100col_1808_101
KU ScholarWorks
author
Wu, Runzhi
author
Smidansky, Eric D.
author
Oh, Hyung Suk
author
Takhampunya, Ratree
author
Padmanabhan, Radhakrishnan
author
Cameron, Craig E.
author
Peterson, Blake R.
2017-04-12T15:58:50Z
2017-04-12T15:58:50Z
2010-11-25
Wu, R., Smidansky, E. D., Oh, H. S., Takhampunya, R., Padmanabhan, R., Cameron, C. E., & Peterson, B. R. (2010). Synthesis of a 6-Methyl-7-Deaza Analogue of Adenosine that Potently Inhibits Replication of Polio and Dengue Viruses. Journal of Medicinal Chemistry, 53(22), 7958–7966. http://doi.org/10.1021/jm100593s
http://hdl.handle.net/1808/23631
10.1021/jm100593s
Bioisosteric deaza analogues of 6-methyl-9-β-D-ribofuranosylpurine, a hydrophobic analogue of adenosine, were synthesized and evaluated for antiviral activity. Whereas the 1-deaza and 3-deaza analogues were essentially inactive in plaque assays of infectivity, a novel 7-deaza-6-methyl-9-β-D-ribofuranosylpurine analogue, structurally related to the natural product tubercidin, potently inhibited replication of poliovirus (PV) in HeLa cells (IC50 = 11 nM) and dengue virus (DENV) in Vero cells (IC50 = 62 nM). Selectivity against PV over cytotoxic effects to HeLa cells was >100-fold after incubation for 7 h. Mechanistic studies of the 5'-triphosphate of 7-deaza-6-methyl-9-β-D-ribofuranosylpurine revealed that this compound is an efficient substrate of PV RNA-dependent RNA polymerase (RdRP) and is incorporated into RNA mimicking both ATP and GTP.
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm100593s.
Synthesis of a 6-Methyl-7-Deaza Analogue of Adenosine that Potently Inhibits Replication of Polio and Dengue Viruses
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23631/1/Peterson_2010.pdf
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oai:kuscholarworks.ku.edu:1808/327532022-05-05T08:00:59Zcom_1808_100col_1808_101
KU ScholarWorks
author
Pope, Chad A.
author
Wilkins, Heather M.
author
Swerdlow, Russell H.
author
Wolfe, Michael S.
2022-05-04T15:23:52Z
2022-05-04T15:23:52Z
2021-09-28
Pope, C. A., Wilkins, H. M., Swerdlow, R. H., & Wolfe, M. S. (2021). Mutations in the Amyloid-β Protein Precursor Reduce Mitochondrial Function and Alter Gene Expression Independent of 42-Residue Amyloid-β Peptide. Journal of Alzheimer's disease : JAD, 83(3), 1039–1049. https://doi.org/10.3233/JAD-210366
http://hdl.handle.net/1808/32753
10.3233/JAD-210366
PMC8917676
Background:Dominant missense mutations in the amyloid-β protein precursor (AβPP) cause early-onset familial Alzheimer’s disease (FAD) and are associated with changes in the production or properties of the amyloid-β peptide (Aβ), particularly of the 42-residue variant (Aβ42) that deposits in the Alzheimer’s disease (AD) brain. Recent findings, however, show that FAD mutations in AβPP also lead to increased production of longer Aβ variants of 45–49 residues in length. Objective:We aimed to test neurotoxicity of Aβ42 vis-á-vis longer variants, focusing specifically on mitochondrial function, as dysfunctional mitochondria are implicated in the pathogenesis of AD. Methods:We generated SH-SY5Y human neuroblastoma cells stably expressing AβPP mutations that lead to increased production of long Aβ peptides with or without Aβ42. These AβPP-expressing cells were tested for oxygen consumption rates (OCR) under different conditions designed to interrogate mitochondrial function. These cell lines were also examined for expression of genes important for mitochondrial or neuronal structure and function. Results:The mutant AβPP-expressing cells showed decreased basal OCRs as well as decreased OCRs associated with mitochondrial ATP production, even more so in the absence of Aβ42 production. Moreover, mutant AβPP-expressing cells producing longer forms of Aβ displayed altered expression of certain mitochondrial- and neuronal-associated genes, whether or not Aβ42 was produced. Conclusion:These findings suggest that mutant AβPP can cause mitochondrial dysfunction that is associated with long Aβ but not with Aβ42.
Copyright The Authors (2021).
Mutagenesis
ELISAs
Oxygen consumption rates
ATP
RNA analysis
Mutations in the Amyloid-β Protein Precursor Reduce Mitochondrial Function and Alter Gene Expression Independent of 42-Residue Amyloid-β Peptide
Article
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URL
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oai:kuscholarworks.ku.edu:1808/238972018-11-28T17:46:48Zcom_1808_100col_1808_101
KU ScholarWorks
author
Lovell, Kimberly M.
author
Vasiljevik, Tamara
author
Araya, Juan Jose
author
Lozama, Anthony
author
Prevatt-Smith, Katherine M.
author
Day, Victor W.
author
Dersch, Christina M.
author
Rothman, Richard B.
author
Butelman, Eduardo R.
author
Kreek, Mary Jeanne
author
Prisinzano, Thomas E.
2017-05-04T19:40:11Z
2017-05-04T19:40:11Z
2012-05-01
Lovell, K. M., Vasiljevik, T., Araya, J. J., Lozama, A., Prevatt-Smith, K. M., Day, V. W., … Prisinzano, T. E. (2012). Semisynthetic Neoclerodanes as Kappa Opioid Receptor Probes. Bioorganic & Medicinal Chemistry, 20(9), 3100–3110. http://doi.org/10.1016/j.bmc.2012.02.040
http://hdl.handle.net/1808/23897
10.1016/j.bmc.2012.02.040
https://orcid.org/0000-0003-4525-7291
PMC3344910
Modification of the furan ring of salvinorin A (1), the main active component of Salvia divinorum, has resulted in novel neoclerodane diterpenes with opioid receptor affinity and activity. Conversion of the furan ring to an aldehyde at the C-12 position (5) has allowed for the synthesis of analogues with new carbon-carbon bonds at that position. Previous methods for forming these bonds, such as Grignard and Stille conditions, have met with limited success. We report a palladium catalyzed Liebeskind-Srogl cross-coupling reaction of a thioester and a boronic acid that occurs at neutral pH and ambient temperature to produce ketone analogs at C-12. To the best of our knowledge, this is the first reported usage of the Liebeskind-Srogl reaction to diversify a natural product scaffold. We also describe a one-step protocol for the conversion of 1 to 12-epi-1 (3) through microwave irradiation. Previously, this synthetically challenging process has required multiple steps. Additionally, we report in this study that alkene 9 and aromatic analogues 12, 19, 23, 25, and 26 were discovered to retain affinity and selectivity at kappa opioid receptors (KOP). Finally, we report that the furan-2-yl analog of 1 (31) has similar affinity to 1. Collectively, these findings suggest that different aromatic groups appended directly to the decalin core may be well tolerated by KOP receptors, and may generate further ligands with affinity and activity at KOP receptors.
This article is made available under an Attribution-NonCommercial-NoDerivs 3.0 United States (CC BY-NC-ND 3.0 US) License.
Semisynthetic Neoclerodanes as Kappa Opioid Receptor Probes
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23897/3/Lovell_Elsevier_2012.pdf
File
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URL
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oai:kuscholarworks.ku.edu:1808/236322019-04-12T14:13:27Zcom_1808_100col_1808_101
KU ScholarWorks
author
Kusuma, Bhaskar Reddy
author
Peterson, Laura B.
author
Zhao, Huiping
author
Vielhauer, George A.
author
Holzbeierlein, Jeffery M.
author
Blagg, Brian S. J.
2017-04-12T16:15:35Z
2017-04-12T16:15:35Z
2011-09-22
Kusuma, B. R., Peterson, L. B., Zhao, H., Vielhauer, G., Holzbeierlein, J., & Blagg, B. S. J. (2011). Targeting the Heat Shock Protein 90 Dimer with Dimeric Inhibitors. Journal of Medicinal Chemistry, 54(18), 6234–6253. http://doi.org/10.1021/jm200553w
http://hdl.handle.net/1808/23632
10.1021/jm200553w
The design, synthesis and biological evaluation of conformationally constrained coumermycin A1 analogues are reported. Compounds were evaluated against both breast cancer (SKBr3 and MCF7) and prostate cancer (PC3mm2, A549 and HT29) cell lines. Non-noviosylated coumermycin A1 analogues that manifest potent anti-proliferative activity resulting from Hsp90 inhibition are provided, wherein replacement of the stereochemically complex noviose sugar with readily available piperidine rings resulted in ~100 fold increase in anti-proliferative activities as compared to coumermycin A1, producing small molecule Hsp90 inhibitors that exhibit nanomolar activities.
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm200553w.
Targeting the Heat Shock Protein 90 Dimer with Dimeric Inhibitors
Article
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URL
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oai:kuscholarworks.ku.edu:1808/225872019-04-12T14:17:28Zcom_1808_100col_1808_101
KU ScholarWorks
author
Samadi, Abbas K.
author
Tong, Xiaoqin
author
Mukerji, Ridhwi
author
Zhang, Huaping
author
Timmermann, Barbara N.
author
Cohen, Mark S.
2017-01-11T20:16:19Z
2017-01-11T20:16:19Z
2010-08-20
Samadi, Abbas K., Xiaoqin Tong, Ridhwi Mukerji, Huaping Zhang, Barbara N. Timmermann, and Mark S. Cohen. "Withaferin A, a Cytotoxic Steroid FromVassobia Breviflora, Induces Apoptosis in Human Head and Neck Squamous Cell Carcinoma." Journal of Natural Products 73.9 (2010): 1476-481.
http://hdl.handle.net/1808/22587
10.1021/np100112p
As part of a program to discover drug leads from plant biodiversity, the present investigation was undertaken to explore the anticancer potential of compounds derived from selected Latin American plants. Bioassay-guided fractionation of a crude extract of the aerial parts of Vassobia breviflora led to the isolation of the withanolide-type steroidal lactone withaferin A (1). This compound was tested for antiproliferative activity against the head and neck squamous cell carcinoma (HNSCC) cell lines, MDA1986, JMAR, UM-SCC-2, and JHU011. The inhibitory concentrations to reduce cell viability to 50% (IC50) were determined by the MTS cytotoxicity assay, and 1 reduced cell viability with IC50 values in the range 0.5−2.2 μM. A mechanistic study showed that 1 induces apoptosis and cell death in HNSCC cells as well as a cell-cycle shift from G0/G1 to G2/M. Cells treated with 1 exhibited inactivation of Akt and a reduction in total Akt concentration. This investigation constitutes the first report of the antiproliferative activity of withaferin A (1) against head and neck squamous carcinoma.
Copyright © 2010 The American Chemical Society and American Society of Pharmacognosy
Withaferin A, a Cytotoxic Steroid from Vassobia breWiflora, Induces Apoptosis in Human Head and Neck Squamous Cell Carcinoma
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/22587/1/timmermann_withaferin.pdf
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URL
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oai:kuscholarworks.ku.edu:1808/243822019-04-12T14:18:34Zcom_1808_100col_1808_101
KU ScholarWorks
author
Szostak, Michal
author
Yao, Lei
author
Day, Victor W.
author
Powell, Douglas R.
author
Aubé, Jeffrey
2017-06-06T16:37:45Z
2017-06-06T16:37:45Z
2010-07-07
Szostak, M., Yao, L., Day, V. W., Powell, D. R., & Aubé, J. (2010). Structural Characterization of N-Protonated Amides. Regioselective N-Activation of Medium-Bridged Twisted Lactams. Journal of the American Chemical Society, 132(26), 8836–8837. http://doi.org/10.1021/ja101690u
http://hdl.handle.net/1808/24382
10.1021/ja101690u
https://orcid.org/0000-0003-1049-5767https://orcid.org/0000-0001-7133-468X
PMC2920036
The straightforward protonation of lactams by treatment with acid and the full structural characterization of three resulting N-protonated lactams are disclosed. This work provides experimental evidence that N-protonation of amide bonds results in a dramatic increase of non-planarity about the C-N amide bond. The resulting compounds are discussed in structural, spectroscopic, and reactivity terms. The data suggests that ca. 50° distortion of these amide bonds suffices for their efficient N-activation.
Structural Characterization of N-Protonated Amides. Regioselective N-Protonated Amides. Regioselective N-Activation of Medium-Bridged Twisted Lactams
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/24382/1/Szostak_2010.pdf
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oai:kuscholarworks.ku.edu:1808/235532018-07-17T15:23:03Zcom_1808_100col_1808_101
KU ScholarWorks
author
Lamb, Kenneth
author
Tidgewell, Kevin
author
Simpson, Denise S.
author
Bohn, Laura M.
author
Prisinzano, Thomas E.
2017-03-31T19:39:17Z
2017-03-31T19:39:17Z
2011-11-26
Lamb, Kenneth, Kevin Tidgewell, Denise S. Simpson, Laura M. Bohn, and Thomas E. Prisinzano. "Antinociceptive Effects of Herkinorin, a MOP Receptor Agonist Derived from Salvinorin A in the Formalin Test in Rats: New Concepts in Mu Opioid Receptor Pharmacology: From a Symposium on New Concepts in Mu-opioid Pharmacology." Drug and Alcohol Dependence 121.3 (2012): 181-88.
http://hdl.handle.net/1808/23553
10.1016/j.drugalcdep.2011.10.026
Herkinorin is the first μ opioid (MOP) selective agonist derived from salvinorin A, a hallucinogenic natural product. Previous work has shown that, unlike other opioids, herkinorin does not promote the recruitment of β-arrestin-2 to the MOP receptor and does not lead to receptor internalization. This paper presents the first in vivo evaluation of herkinorin’s antinociceptive effects in rats, using the formalin test as a model of tonic inflammatory pain. Herkinorin was found to produce a dose-dependent decrease in the number of flinches evoked by formalin. These antinociceptive effects were substantially blocked by pretreatment with the nonselective antagonist naloxone, indicating that the antinociception is mediated by opioid receptors. Contralateral administration of herkinorin did not attenuate the number of flinches evoked by formalin, indicating that its effects are peripherally restricted to the site of injection. Following chronic administration (5-day), herkinorin maintained antinociceptive efficacy in both phases of the formalin test. Furthermore, unlike morphine, herkinorin was still able to inhibit flinching in both phases of the formalin test in animals made tolerant to chronic systemic morphine treatment. Collectively, these results suggest that herkinorin may produce peripheral antinociception with decreased tolerance liability and thereby represents a promising template for the development of agents for the treatment of a variety of pain states.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
MOP receptors
Herkinorin
β-arrestin-2
Morphine
Tolerance
Formalin
Antinociceptive Effects of Herkinorin, a MOP Receptor Agonist Derived from Salvinorin A in the Formalin Test in Rats: New Concepts in Mu Opioid Receptor Pharmacology
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23553/1/prisinzano_antinociceptive.pdf
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URL
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oai:kuscholarworks.ku.edu:1808/83142019-04-12T14:39:03Zcom_1808_8219com_1808_100col_1808_8220col_1808_101
KU ScholarWorks
author
Xie, Sheng-Xue
author
Huang, Wei-Jun
author
Ma, Ze-Qiang
author
Huang, Min
author
Hanzlik, Robert P.
author
Ye, Qi-Zhuang
2011-10-31T15:47:17Z
2011-10-31T15:47:17Z
2006-04
Xie SX, Huang WJ, Ma ZQ, Huang M, Hanzlik RP, Ye QZ, "Structural analysis of metalloform-selective inhibition of methionine aminopeptidase." Acta Cryst., D62, 425-432 (2006). PMID: 16552144 http://dx.doi.org/10.1107/S0907444906003878
http://hdl.handle.net/1808/8314
10.1107/S0907444906003878
One of the challenges in the development of methionine aminopeptidase (MetAP) inhibitors as antibacterial and anticancer agents is to define the metal ion actually used by MetAP in vivo and to discover MetAP inhibitors that can inhibit the metalloform that is relevant in vivo. Two distinct classes of novel nonpeptidic MetAP inhibitors that are not only potent but also highly selective for either the MnII or CoII form have been identified. Three crystal structures of Escherichia coli MetAP complexed with the metalloform-selective inhibitors 5-(2,5-dichlorophenyl)furan-2-carboxylic acid (2), 5-[2-(trifluoromethyl)phenyl]furan-2-carboxylic acid (3) and N-cyclopentyl-N-(thiazol-2-yl)oxalamide (4) have been solved and analysis of these structures has revealed the structural basis for their metalloform-selective inhibition. The MnII-form selective inhibitors (2) and (3) both use their carboxylate group to coordinate with the two MnII ions at the dinuclear metal site and both adopt a non-coplanar conformation for the two aromatic rings. The unique coordination geometry of these inhibitors may determine their MnII-form selectivity. In contrast, the CoII-form selective inhibitor (4) recruits an unexpected third metal ion, forming a trimetallic enzyme–metal–inhibitor complex. Thus, an important factor in the selectivity of (4) for the CoII form may be a consequence of a greater preference for a softer N,O-donor ligand for the softer CoII.
en_US
Methionine aminopeptidase
Inhibitors
Metalloform-selective inhibition
Structural analysis of metalloform-selective inhibition of methionine aminopeptidase
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/8314/1/ActaCrystal_hanzlik.pdf
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oai:kuscholarworks.ku.edu:1808/324032022-01-15T09:00:56Zcom_1808_100col_1808_101
KU ScholarWorks
author
Zhao, Junxing
author
Qiu, Jianming
author
Aryal, Sadikshya
author
Hackett, Jennifer L.
author
Wang, Jingxin
2022-01-14T21:53:26Z
2022-01-14T21:53:26Z
2020-12-21
Zhao, J.; Qiu, J.; Aryal, S.; Hackett, J.L.; Wang, J. The RNA Architecture of the SARS-CoV-2 3′-Untranslated Region. Viruses 2020, 12, 1473. https://doi.org/10.3390/v12121473
http://hdl.handle.net/1808/32403
10.3390/v12121473
https://orcid.org/ 0000-0002-6305-6218https://orcid.org/ 0000-0001-9850-1695https://orcid.org/ 0000-0002-9414-4093
PMC7766253
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current COVID-19 pandemic. The 3′ untranslated region (UTR) of this β-CoV contains essential cis-acting RNA elements for the viral genome transcription and replication. These elements include an equilibrium between an extended bulged stem-loop (BSL) and a pseudoknot. The existence of such an equilibrium is supported by reverse genetic studies and phylogenetic covariation analysis and is further proposed as a molecular switch essential for the control of the viral RNA polymerase binding. Here, we report the SARS-CoV-2 3′ UTR structures in cells that transcribe the viral UTRs harbored in a minigene plasmid and isolated infectious virions using a chemical probing technique, namely dimethyl sulfate (DMS)-mutational profiling with sequencing (MaPseq). Interestingly, the putative pseudoknotted conformation was not observed, indicating that its abundance in our systems is low in the absence of the viral nonstructural proteins (nsps). Similarly, our results also suggest that another functional cis-acting element, the three-helix junction, cannot stably form. The overall architectures of the viral 3′ UTRs in the infectious virions and the minigene-transfected cells are almost identical.
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.
SARS-CoV-2
COVID-19
DMS
DMS-MaPseq
ShapeKnots
DREEM
Pseudoknot
Three-helix junction
3′ UTR
Minigene
The RNA Architecture of the SARS-CoV-2 3′-Untranslated Region
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/32403/1/Zhao_2020.pdf
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oai:kuscholarworks.ku.edu:1808/236222018-07-17T15:24:49Zcom_1808_100col_1808_101
KU ScholarWorks
author
Gu, Xingxian
author
Georg, Gunda I.
2017-04-10T20:48:45Z
2017-04-10T20:48:45Z
2015-10-21
Gu, Xingxian, and Gunda I. Georg. “Regioselective C5-Alkylation and C5-Methylcarbamate Formation of 2,3-Dihydro-4-Pyridones and C3-Alkylation and C3-Methylcarbamate Formation of 4-(pyrrolidin-1-Yl)furan-2(5H)-One.” Tetrahedron letters 56.43 (2015): 5874–5877.
http://hdl.handle.net/1808/23622
10.1016/j.tetlet.2015.09.004
Reactions of N-alkyl-2,3-dihydro-4-pyridones and 4-(pyrrolidin-1-yl)furan-2(5H)-one with aldehydes and triethylsilane in a one-flask procedure provided C5 and C3 alkylated derivatives, respectively. Mannich-type reactions with formaldehyde and carbamates in the presence of lithium perchlorate furnished C5/C3 methylcarbamates.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
2, 3-dihydro-4pyridones
4-(pyrrolidin-1-yl) furan-2(5H)-one
Regioselective alkylation
Mannich reaction
Regioselective C5-alkylation and C5-methylcarbamate formation of 2,3-dihydro-4-pyridones and C3-alkylation and C3-methylcarbamate formation of 4-(pyrrolidin-1-yl)furan-2(5H)-one
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23622/1/georg_regioselective.pdf
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oai:kuscholarworks.ku.edu:1808/176562019-04-12T14:16:02Zcom_1808_100col_1808_101
KU ScholarWorks
author
David, Sunil A.
author
Silverstein, Richard
author
Amura, Claudia R.
author
Kielian, Tammy
author
Morrison, David C.
2015-05-08T15:19:05Z
2015-05-08T15:19:05Z
1999-04
David, et al. "Lipopolyamines: Novel Antiendotoxin Compounds That Reduce Mortality in Experimental Sepsis Caused by Gram-Negative Bacteria." Antimicrob. Agents Chemother. April 1999 vol. 43 no. 4 912-919.
http://hdl.handle.net/1808/17656
The interactions of lipopolyamines, a class of structurally unique compounds currently being used as transfection (lipofection) agents, with lipopolysaccharide (LPS) have been characterized. Our studies have demonstrated that 1,3-di-oleoyloxy-2-(6-carboxyspermyl)-propylamide), available commercially as DOSPER, binds to purified LPS with an affinity of about 1/10 that of polymyxin B. This essentially nontoxic compound inhibits, in a dose-dependent manner, LPS-induced activation of the Limulus clotting cascade and the production of tumor necrosis factor alpha (TNF-α) interleukin-6 (IL-6), and nitric oxide from LPS-stimulated J774.A1 cells, a murine macrophage-like cell line. Cytokine inhibition is paralleled by decreased steady-state levels of TNF-α and IL-6 mRNA and inhibits the nuclear translocation of nuclear factor kappa B. These findings suggest that the lipopolyamine compound sequesters LPS, thereby blocking downstream cellular activation events that lead to the production of proinflammatory mediators. Administration of DOSPER to d-galactosamine-sensitized mice challenged either with LPS or with Escherichia coliorganisms provided significant protection against lethality both with and without antibiotic chemotherapy. Partial protection is evident in LPS-challenged mice treated with DOSPER as late as 2 to 4 h following the endotoxin challenge. A greater degree of protection is observed in E. coli-challenged animals receiving ceftazidime than in those receiving imipenem, which is probably attributable to the higher levels of LPS released in vivo by the former antibiotic. Potent antiendotoxic activity, low toxicity, and ease of synthesis render the lipopolyamines candidate endotoxin-sequestering agents of potential significant therapeutic value.
Lipopolyamines: Novel Antiendotoxin Compounds That Reduce Mortality in Experimental Sepsis Caused by Gram-Negative Bacteria
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/17656/1/DavidS_AAC_43%284%29912.pdf
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oai:kuscholarworks.ku.edu:1808/246902018-07-17T16:11:14Zcom_1808_100col_1808_101
KU ScholarWorks
author
Butelman, Eduardo R.
author
Rus, Szymon
author
Prisinzano, Thomas E.
author
Kreek, Mary Jeanne
2017-06-28T19:41:06Z
2017-06-28T19:41:06Z
2010-06
Butelman, E. R., Rus, S., Prisinzano, T. E., & Kreek, M. J. (2010). The discriminative effects of the κ-opioid hallucinogen salvinorin A in nonhuman primates: dissociation from classic hallucinogen effects. Psychopharmacology, 210(2), 253–262. http://doi.org/10.1007/s00213-009-1771-5
http://hdl.handle.net/1808/24690
10.1007/s00213-009-1771-5
PMC2866021
RATIONALE: The widely available hallucinogen salvinorin A is a unique example of a plant-derived compound selective for κ-opioid receptors and may produce effects distinct from those of other compounds with classic hallucinogenic or dissociative properties which are also abused in humans. OBJECTIVES: The objective of this study is to characterize the salvinorin A discriminative cue in nonhuman primates with high κ-receptor genetic homology to humans. METHODS: Adult rhesus monkeys (n=3) were trained to discriminate salvinorin A (0.015 mg/kg, s.c.) from vehicle, in a food-reinforced operant discrimination assay. Parallel studies, using unconditioned behavioral endpoints (facial relaxation and ptosis) also evaluated the κ-opioid receptor mediation of salvinorin A in vivo function. RESULTS: Monkeys trained to discriminate salvinorin A generalized structurally diverse, centrally penetrating κ-agonists (bremazocine, U69,593, and U50,488). By contrast, μ- and δ-opioid agonists (fentanyl and SNC80, respectively) were not generalized, nor were the serotonergic 5HT2 hallucinogen psilocybin or the dissociative N-methyl-D-aspartic acid antagonist, ketamine. The discriminative effects of salvinorin A were blocked by the opioid antagonist quadazocine (0.32 mg/kg), but not by the 5HT2 antagonist ketanserin (0.1 mg/kg). Consistent with these findings, salvinorin and κ-agonists (e.g., U69,593) produce effects in the unconditioned endpoints (e.g., ptosis), whereas psilocybin was inactive. Conclusions: These findings support the conclusion that the interoceptive/discriminative cue produced by salvinorin A is mediated by agonism at κ-receptors and is mechanistically distinct from that produced by a classic serotonergic hallucinogen.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 4.0 (CC BY-NC-ND 4.0), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Dynorphin
κ-opioid
Hallucinogen
Opioid
Salvinorin A
Salvia divinorum
The discriminative effects of the κ-opioid hallucinogen salvinorin A in nonhuman primates: dissociation from classic hallucinogen effects
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/24690/1/Prisinzano_2010.pdf
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oai:kuscholarworks.ku.edu:1808/236912019-04-12T14:13:59Zcom_1808_100col_1808_101
KU ScholarWorks
author
Niphakis, Micah James
author
Turunen, Brandon J.
author
Georg, Gunda I.
2017-04-13T17:28:05Z
2017-04-13T17:28:05Z
2010-10-15
Niphakis, M. J., Turunen, B. J., & Georg, G. I. (2010). Synthesis of 6- and 7-membered cyclic enaminones: Scope and mechanism. The Journal of Organic Chemistry, 75(20), 6793–6805. http://doi.org/10.1021/jo100907u
http://hdl.handle.net/1808/23691
10.1021/jo100907u
Six- and seven-membered cyclic enaminones can be prepared using common, environmentally benign reagents. Amino acids are used as synthetic precursors allowing diversification and the incorporation of chirality. The key reaction in this multi-step process involves deprotection of Boc-aminoynones and subsequent treatment with methanolic K2CO3 to induce cyclization. A β-amino elimination side reaction was identified in a few labile substrates that led to either loss of stereochemical purity or degradation. This process can be mitigated in specific cases using mild deprotection conditions. NMR and deuterium labeling experiments provided valuable insight into the workings and limitations of this reaction. Although disguised as a 6-endo-dig cyclization, the reagents employed in the transformation play a direct role in bond-making and bond-breaking, thus changing the mode of addition to a 6-endo-trig cyclization. This method can be used to construct an array of monocyclic and bicyclic scaffolds, many of which are found in well-known natural products (e.g. indolizidine, quinolizidine and Stemona alkaloids).
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Organic Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jo100907u.
Enaminone
Vinylogous amide
Ynone
6-endo-trig
6-endo-dig
6-exo-trig
®-amino elimination
Retro-Michael
3-dihydro-4-pyridone
Azepine
Boc-deprotection
Synthesis of 6- and 7-membered cyclic enaminones: Scope and mechanism
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23691/1/Niphakis_2010.pdf
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Niphakis_2010.pdf.txt
oai:kuscholarworks.ku.edu:1808/236332019-04-12T14:13:35Zcom_1808_100col_1808_101
KU ScholarWorks
author
Patkar, Kshitij A.
author
Murray, Thomas F.
author
Aldrich, Jane V.
2017-04-12T16:27:02Z
2017-04-12T16:27:02Z
2009-11-12
Patkar, K. A., Murray, T. F., & Aldrich, J. V. (2009). The Effects of C-terminal Modifications on the Opioid Activity of [N-BenzylTyr1]Dynorphin A-(1-11) Analogs. Journal of Medicinal Chemistry, 52(21), 6814–6821. http://doi.org/10.1021/jm900715m
http://hdl.handle.net/1808/23633
10.1021/jm900715m
Structural modifications affecting the efficacy of analogs of the endogenous opioid peptide dynorphin (Dyn) A have focused on the N-terminal “message” sequence, based on the “messageaddress” concept. To test the hypothesis that changes in the C-terminal “address” domain could affect efficacy, modified amino acids and cyclic constraints were incorporated into this region of the partial agonist [N-benzylTyr1]Dyn A-(1-11). Modifications in the C-terminal domain of [NbenzylTyr1] Dyn A-(1-11)NH2 resulted in increased kappa opioid receptor (KOR) affinity for all of the linear analogs, but did not affect the efficacy of these peptides at KOR. Cyclization between positions 5 and 8 yielded [N-benzylTyr1,cyclo(D-Asp5,Dap8)]Dyn A-(1-11)NH2 (13) (Patkar et al. J. Med. Chem. 2005, 48, 4500-4503) with high selectivity for KOR. In contrast to the linear peptides, this peptide exhibits negligible efficacy in the AC assay and is a KOR antagonist. These data are consistent with our hypothesis that appropriate modifications in the “address” domain of Dyn A analogs may affect efficacy.
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm900715m.
The Effects of C-terminal Modifications on the Opioid Activity of [N-BenzylTyr1]Dynorphin A-(1-11) Analogs
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23633/1/Patkar_2009.pdf
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oai:kuscholarworks.ku.edu:1808/271292018-11-05T16:16:19Zcom_1808_100col_1808_101
KU ScholarWorks
author
Pashikanti, Srinath
author
Ukani, Rehman
author
David, Sunil A.
author
Datta, Apurba
2018-11-01T18:00:49Z
2018-11-01T18:00:49Z
2017
Pashikanti, S., Rehnman, U., David, S. A., Apurba, D., (2017), FTotal Synthesis and Structure–Activity Relationship Studies of the Cytotoxic Anhydrophytosphingosine Jaspine B (Pachastrissamine), Synthesis, https://doi.org/10.1055/s-0036-1588118
http://hdl.handle.net/1808/27129
10.1055/s-0036-1588118
By utilizing an l-serine-derived bicyclic lactone as an advanced chiral building block, a short synthetic route to the cytotoxic marine natural product jaspine B has been developed. Targeting structure–activity relationship investigations, the synthetic route has also been utilized for the synthesis and cytotoxicity evaluation of strategically modified jaspine B analogues. In addition, a previously reported synthesis of the title natural product from our research has been reinvestigated to clarify the sterochemical assignment.
Jaspine B
Stereochemistry
Cytotoxic
Drug development
Structure
Activity relationships
Total Synthesis and Structure–Activity Relationship Studies of the Cytotoxic Anhydrophytosphingosine Jaspine B (Pachastrissamine)
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/27129/1/Pashikanti_2017.pdf
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oai:kuscholarworks.ku.edu:1808/259012018-06-13T16:57:13Zcom_1808_100col_1808_101
KU ScholarWorks
author
Samadi, Abbas K.
author
Zhang, Xuan
author
Mukerji, Ridhwi
author
Donnelly, Alison C.
author
Blagg, Brian S. J.
author
Cohen, Mark S.
2018-02-01T18:15:33Z
2018-02-01T18:15:33Z
2011-12-22
Samadi, A. K., Zhang, X., Mukerji, R., Donnelly, A. C., Blagg, B. S., & Cohen, M. S. (2011). A novel C-terminal HSP90 inhibitor KU135 induces apoptosis and cell cycle arrest in melanoma cells. Cancer Letters, 312(2), 158–167. http://doi.org/10.1016/j.canlet.2011.07.031
http://hdl.handle.net/1808/25901
10.1016/j.canlet.2011.07.031
PMC5683962
Heat shock protein 90 (Hsp90) is differentially expressed in tumor cells including melanoma and involved in proper folding, stabilization and regulation of cellular proteins. We investigated a novobiocin-derived Hsp90 C-terminal inhibitor, KU135, for anti-proliferative effects in melanoma cells. The results indicate that KU135 reduced cell viability and cell proliferation in melanoma cells and IC50 values for A735(DRO), M14(NPA), B16F10 and SKMEL28 cells were 0.82, 0.92, 1.33 and 1.30 M respectively. KU135 induced a more potent anti-proliferative effect in most melanoma cells versus N-terminal Hsp90 inhibitor 17AAG. KU135 induced apoptosis in melanoma cells, as indicated by annexin V/PI staining, reduction in the mitochondrial membrane potential, mitochondrial cytochrome C release and caspase 3 activation. KU135 reduced levels of Hsp90 client proteins Akt, BRAF, RAF-1, cyclin B and cdc25 proteins. Additionally, it reduced Hsp70, Hsp90 paralog, GRP94 and HSF1 levels. KU135 induced strong G2/M cell cycle arrest, associated with decreased expression of cdc25c, cyclin B and increased phosphorylation of cdc25c. These finding show that KU135 reduced cell survival, proliferation, and induces apoptosis in melanoma cells. We suggest that KU135 may be a potential candidate for cancer therapy against melanoma.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 4.0 (CC BY-NC-ND 4.0), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Hsp90 inhibitor
C-terminal
Melanoma
A novel C-terminal HSP90 inhibitor KU135 induces apoptosis and cell cycle arrest in melanoma cells
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/25901/1/Donnelly_2011.pdf
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oai:kuscholarworks.ku.edu:1808/343752023-06-14T06:05:55Zcom_1808_100col_1808_101
KU ScholarWorks
author
Nagamalla, Someshwar
author
Mague, Joel T.
author
Sathyamoorthi, Shyam
2023-06-13T20:54:06Z
2023-06-13T20:54:06Z
2023-02-06
Nagamalla, S., Mague, J. T., & Sathyamoorthi, S. (2023). Covalent Tethers for Precise Amino Alcohol Syntheses: Ring Opening of Epoxides by Pendant Sulfamates and Sulfamides. Organic letters, 25(6), 982–986. https://doi.org/10.1021/acs.orglett.3c00053
https://hdl.handle.net/1808/34375
10.1021/acs.orglett.3c00053
https://orcid.org/0000-0003-4705-7349
PMC10017054
We describe the development of the first ring opening of epoxides using pendant sulfamates and sulfamides. These reactions are promoted by a base and proceed under mild conditions to afford oxathiazinanes and cyclic sulfamides with excellent diastereoselectivity and regiocontrol. The reactions scale well, and the products serve as synthons for ring-opening reactions.
Copyright © 2023 American Chemical Society
Cyclization
Ethers
Mixtures
Ring opening reactions
Substitution reactions
Covalent Tethers for Precise Amino Alcohol Syntheses: Ring Opening of Epoxides by Pendant Sulfamates and Sulfamides
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/34375/1/Nagamalla_2023.pdf
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oai:kuscholarworks.ku.edu:1808/311802021-01-19T09:00:48Zcom_1808_100col_1808_101
KU ScholarWorks
author
Liu, Lei
author
Ding, Li
author
Rovere, Matteo
author
Wolfe, Michael S.
author
Selkoe, Dennis J.
2021-01-18T21:21:55Z
2021-01-18T21:21:55Z
2019-01-09
Lei Liu, Li Ding, Matteo Rovere, Michael S. Wolfe, Dennis J. Selkoe; A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor. J Cell Biol 4 February 2019; 218 (2): 644–663. doi: https://doi.org/10.1083/jcb.201806205
http://hdl.handle.net/1808/31180
10.1083/jcb.201806205
https://orcid.org/0000-0002-4604-4629https://orcid.org/0000-0002-3260-4955https://orcid.org/0000-0001-8846-9767
Intramembrane proteolysis of transmembrane substrates by the presenilin–γ-secretase complex is preceded and regulated by shedding of the substrate’s ectodomain by α- or β-secretase. We asked whether β- and γ-secretases interact to mediate efficient sequential processing of APP, generating the amyloid β (Aβ) peptides that initiate Alzheimer’s disease. We describe a hitherto unrecognized multiprotease complex containing active β- and γ-secretases. BACE1 coimmunoprecipitated and cofractionated with γ-secretase in cultured cells and in mouse and human brain. An endogenous high molecular weight (HMW) complex (∼5 MD) containing β- and γ-secretases and holo-APP was catalytically active in vitro and generated a full array of Aβ peptides, with physiological Aβ42/40 ratios. The isolated complex responded properly to γ-secretase modulators. Alzheimer’s-causing mutations in presenilin altered the Aβ42/40 peptide ratio generated by the HMW β/γ-secretase complex indistinguishably from that observed in whole cells. Thus, Aβ is generated from holo-APP by a BACE1–γ-secretase complex that provides sequential, efficient RIP processing of full-length substrates to final products.
© 2019 Liu et al.
Biochemistry
Neuroscience
Protein homeostasis
A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor
Article
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https://kuscholarworks.ku.edu/bitstream/1808/31180/1/Liu_2019.pdf
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oai:kuscholarworks.ku.edu:1808/86332019-04-12T14:43:21Zcom_1808_8219com_1808_100col_1808_8220col_1808_101
KU ScholarWorks
author
Auld, Douglas S.
author
Lovell, Scott
author
Thorne, Natasha
author
Lea, Wendy A.
author
Maloney, David J.
author
Shen, Min
author
Rai, Ganesha
author
Battaile, Kevin P.
author
Thomas, Craig J.
author
Simeonov, Anton
author
Hanzlik, Robert P.
author
Inglese, James
2011-12-19T16:23:41Z
2011-12-19T16:23:41Z
2010-03-16
Douglas S. Auld, Scott Lovell, Natasha Thorne, Wendy A. Lea, David J. Maloney, Min Shen, Ganesha Rai, Kevin Battaile, Craig J. Thomas, Anton Simeonov, Robert P. Hanzlik, and James Inglese, "Molecular Basis for the High Affinity Binding and Stabilization of Firefly Luciferase by PTC124." Proc. Nat. Acad. Sci. USA 2010, 107, 4878-83. PMID 20194791 http://dx.doi.org/10.1073/pnas.0909141107
http://hdl.handle.net/1808/8633
10.1073/pnas.0909141107
Firefly luciferase (FLuc), an ATP-dependent bioluminescent reporter enzyme, is broadly used in chemical biology and drug discovery assays. PTC124 (Ataluren; (3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid) discovered in an FLuc-based assay targeting nonsense codon suppression, is an unusually potent FLuc-inhibitor. Paradoxically, PTC124 and related analogs increase cellular FLuc activity levels by posttranslational stabilization. In this study, we show that FLuc inhibition and stabilization is the result of an inhibitory product formed during the FLuc-catalyzed reaction between its natural substrate, ATP, and PTC124. A 2.0 Å cocrystal structure revealed the inhibitor to be the acyl-AMP mixed-anhydride adduct PTC124-AMP, which was subsequently synthesized and shown to be a high-affinity multisubstrate adduct inhibitor (MAI; KD = 120 pM) of FLuc. Biochemical assays, liquid chromatography/mass spectrometry, and near-attack conformer modeling demonstrate that formation of this novel MAI is absolutely dependent upon the precise positioning and reactivity of a key meta-carboxylate of PTC124 within the FLuc active site. We also demonstrate that the inhibitory activity of PTC124-AMP is relieved by free coenzyme A, a component present at high concentrations in luciferase detection reagents used for cell-based assays. This explains why PTC124 can appear to increase, instead of inhibit, FLuc activity in cell-based reporter gene assays. To our knowledge, this is an unusual example in which the “off-target” effect of a small molecule is mediated by an MAI mechanism.
en_US
Ataluren
Multi-substrate adduct inhibitor
X-ray crystallography
Protein stability
Molecular Basis for the High Affinity Binding and Stabilization of Firefly Luciferase by PTC124
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/8633/1/1.%20Auld%20et%20al_PNAS_combined100108%20copy.pdf
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URL
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oai:kuscholarworks.ku.edu:1808/244972019-04-12T14:19:49Zcom_1808_100col_1808_101
KU ScholarWorks
author
Grogan, Patrick T.
author
Sleder, Kristina D.
author
Samadi, Abbas K.
author
Timmermann, Barbara N.
author
Cohen, Mark S.
2017-06-13T20:39:35Z
2017-06-13T20:39:35Z
2013-06
Grogan, P.T., Sleder, K.D., Samadi, A.K. et al. Invest New Drugs (2013) 31: 545. doi:10.1007/s10637-012-9888-5
http://hdl.handle.net/1808/24497
10.1007/s10637-012-9888-5
PMC3677827
Withaferin A (WA), a steroidal lactone derived from the plant Vassobia breviflora, has been reported to have anti-proliferative, pro-apoptotic, and anti-angiogenic properties against cancer growth. In this study, we identified several key underlying mechanisms of anticancer action of WA in glioblastoma cells. WA was found to inhibit proliferation by inducing a dose-dependent G2/M cell cycle arrest and promoting cell death through both intrinsic and extrinsic apoptotic pathways. This was accompanied by an inhibitory shift in the Akt/mTOR signaling pathway which included diminished expression and/or phosphorylation of Akt, mTOR, p70 S6K, and p85 S6K with increased activation of AMPKα and the tumor suppressor tuberin/TSC2. Alterations in proteins of the MAPK pathway and cell surface receptors like EGFR, Her2/ErbB2, and c-Met were also observed. WA induced an N-acetyl-L-cysteinerepressible enhancement in cellular oxidative potential/stress with subsequent induction of a heat shock stress response primarily through HSP70, HSP32, and HSP27 upregulation and HSF1 downregulation. Taken together, we suggest that WA may represent a promising chemotherapeutic candidate in glioblastoma therapy warranting further translational evaluation.
© Springer Science+Business Media New York 2012
Withaferin A
Glioblastoma multiforme
Oxidative stress
Heat shock response
Akt/mTOR pathway
MAPK pathway
Cytotoxicity of withaferin A in glioblastomas involves induction of an oxidative stress-mediated heat shock response while altering Akt/mTOR and MAPK signaling pathways
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/24497/1/Timmermann_2013.pdf
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oai:kuscholarworks.ku.edu:1808/342612023-06-02T06:05:45Zcom_1808_100col_1808_101
KU ScholarWorks
author
Shinde, Anand H.
author
Sathyamoorthi, Shyam
2023-06-01T14:08:17Z
2023-06-01T14:08:17Z
2020-01-13
Shinde, A. H., & Sathyamoorthi, S. (2020). Oxidative Cyclization of Sulfamates onto Pendant Alkenes. Organic letters, 22(3), 896–901. https://doi.org/10.1021/acs.orglett.9b04448
https://hdl.handle.net/1808/34261
10.1021/acs.orglett.9b04448
https://orcid.org/0000-0003-4705-7349
PMC10117694
This communication discloses the first examples of aza-Wacker cyclizations of sulfamate esters. Within the realm of related cyclization reactions, this protocol is differential in that it forms six-membered rings in good yield and uses catalytic amounts of palladium(0) rather than palladium(II) salts. These reactions scale well, and their products are demonstrated to be valuable synthetic intermediates.
Copyright © 2020 American Chemical Society.
Oxidative Cyclization of Sulfamates onto Pendant Alkenes
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/34261/1/Shinde_2023.pdf
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oai:kuscholarworks.ku.edu:1808/271872018-12-27T17:03:17Zcom_1808_100col_1808_101
KU ScholarWorks
author
Herschhorn, Alon
author
Gu, Christopher
author
Moraca, Francesca
author
Ma, Xiaochu
author
Farrell, Mark
author
Smith, Amos B., III
author
Pancera, Marie
author
Kwong, Peter D.
author
Schön, Arne
author
Freire, Ernesto
author
Abrams, Cameron
author
Blanchard, Scott C.
author
Mothes, Walther
author
Sodroski, Joseph G.
2018-11-02T18:16:26Z
2018-11-02T18:16:26Z
2017-10-19
Herschhorn, A., 2017. The β20–β21 of gp120 is a regulatory switch for HIV-1 Env conformational transitions. Nature Research, https://doi.org/10.1038/s41467-017-01119-w
http://hdl.handle.net/1808/27187
10.1038/s41467-017-01119-w
The entry of HIV-1 into target cells is mediated by the viral envelope glycoproteins (Env). Binding to the CD4 receptor triggers a cascade of conformational changes in distant domains that move Env from a functionally “closed” State 1 to more “open” conformations, but the molecular mechanisms underlying allosteric regulation of these transitions are still elusive. Here, we develop chemical probes that block CD4-induced conformational changes in Env and use them to identify a potential control switch for Env structural rearrangements. We identify the gp120 β20–β21 element as a major regulator of Env transitions. Several amino acid changes in the β20–β21 base lead to open Env conformations, recapitulating the structural changes induced by CD4 binding. These HIV-1 mutants require less CD4 to infect cells and are relatively resistant to State 1-preferring broadly neutralizing antibodies. These data provide insights into the molecular mechanism and vulnerability of HIV-1 entry.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
The β20–β21 of gp120 is a regulatory switch for HIV-1 Env conformational transitions
Article
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URL
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oai:kuscholarworks.ku.edu:1808/176532019-04-16T16:51:45Zcom_1808_100col_1808_101
KU ScholarWorks
author
Sil, Diptesh
author
Shrestha, Anurupa
author
Kimbrell, Matthew R.
author
Nguyen, Thuan B.
author
Adisechan, Ashok K.
author
Balakrishna, Rajalakshmi
author
Abbo, Benjamin G.
author
Malladi, Subbalakshmi S.
author
Miller, Kelly A.
author
Short, Shannon
author
Cromer, Jens R.
author
Arora, Shravan
author
Datta, Apurba
author
David, Sunil A.
2015-05-07T21:11:19Z
2015-05-07T21:11:19Z
2007-08
Sil et. al. "Bound To Shock: Protection from Lethal Endotoxemic Shock by a Novel, Nontoxic, Alkylpolyamine Lipopolysaccharide Sequestrant." Antimicrob. Agents Chemother. August 2007 vol. 51 no. 8 2811-2819.
http://dx.doi.org/10.1128/AAC.00200-07
http://hdl.handle.net/1808/17653
10.1128/AAC.00200-07
https://orcid.org/0000-0001-6457-0545
Lipopolysaccharide (LPS), or endotoxin, a structural component of gram-negative bacterial outer membranes, plays a key role in the pathogenesis of septic shock, a syndrome of severe systemic inflammation which leads to multiple-system organ failure. Despite advances in antimicrobial chemotherapy, sepsis continues to be the commonest cause of death in the critically ill patient. This is attributable to the lack of therapeutic options that aim at limiting the exposure to the toxin and the prevention of subsequent downstream inflammatory processes. Polymyxin B (PMB), a peptide antibiotic, is a prototype small molecule that binds and neutralizes LPS toxicity. However, the antibiotic is too toxic for systemic use as an LPS sequestrant. Based on a nuclear magnetic resonance-derived model of polymyxin B-LPS complex, we had earlier identified the pharmacophore necessary for optimal recognition and neutralization of the toxin. Iterative cycles of pharmacophore-based ligand design and evaluation have yielded a synthetically easily accessible N1,mono-alkyl-mono-homologated spermine derivative, DS-96. We have found that DS-96 binds LPS and neutralizes its toxicity with a potency indistinguishable from that of PMB in a wide range of in vitro assays, affords complete protection in a murine model of LPS-induced lethality, and is apparently nontoxic in vertebrate animal models.
Bound To Shock: Protection from Lethal Endotoxemic Shock by a Novel, Nontoxic, Alkylpolyamine Lipopolysaccharide Sequestrant
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/17653/1/DavidS_AAC_51%288%292811.pdf
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oai:kuscholarworks.ku.edu:1808/235982019-04-12T14:12:54Zcom_1808_100col_1808_101
KU ScholarWorks
author
Salunke, Deepak B.
author
Yoo, Euna
author
Shukla, Nikunj M.
author
Balakrishna, Rajalakshmi
author
Malladi, Subbalakshmi S.
author
Serafin, Katelyn J.
author
Day, Victor W.
author
Wang, Xinkun
author
David, Sunil A.
2017-04-06T17:54:16Z
2017-04-06T17:54:16Z
2012-09-27
Salunke, D. B., Yoo, E., Shukla, N. M., Balakrishna, R., Malladi, S. S., Serafin, K. J., … David, S. A. (2012). Structure-Activity Relationships in Human Toll-like Receptor 8-Active 2,3-diamino-furo[2,3-c]pyridines. Journal of Medicinal Chemistry, 55(18), 8137–8151. http://doi.org/10.1021/jm301066h
http://hdl.handle.net/1808/23598
10.1021/jm301066h
https://orcid.org/0000-0002-1241-9146
https://orcid.org/0000-0003-1377-0509
In our ongoing search toward identifying novel and synthetically simpler candidate vaccine adjuvants, we hypothesized that the imidazo[1,2-a]pyrazines, readily accessible via the Groebke-Blackburn-Bienaymé multicomponent reaction, would possess sufficient structural similarity with TLR7/8-agonistic imidazoquinolines. With pyridoxal as the aldehyde component, furo[2,3- c]pyridines, rather than the expected imidazo[1,2-a]pyridines were obtained, which were characterized by NMR spectroscopy and crystallography. Several analogues were found to activate TLR8-dependent NF-κB signaling. In a focused library of furo[2,3-c]pyridines, a distinct SAR was observed with varying substituents at C2. In human PBMCs, none of the furo[2,3-c]pyridines showed any proinflammatory cytokine induction, but upregulated several chemokine ligand genes. In immunization studies in rabbits, the most active compound showed prominent adjuvantic effects. The complete lack of proinflammatory cytokine induction coupled with strong adjuvantic activity of the novel furo[2,3-c]pyridines render this hitherto unknown chemotype an attractive class of compounds which are expected to be devoid of local or systemic reactogenicity.
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm301066h.
TLR8
TLR8 agonists
Vaccine adjuvants
Innate immunity
Furopyridines
Structure-Activity Relationships in Human Toll-like Receptor 8-Active 2,3-diamino-furo[2,3-c]pyridines
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23598/1/Yoo_2012.pdf
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oai:kuscholarworks.ku.edu:1808/309512020-12-03T09:00:48Zcom_1808_100com_1808_981col_1808_101col_1808_982
KU ScholarWorks
author
Petschenka, Georg
author
Fei, Colleen S.
author
Araya, Juan J.
author
Schröder, Susanne
author
Timmermann, Barbara N.
author
Agrawal, Anurag A.
2020-12-02T14:46:39Z
2020-12-02T14:46:39Z
2018-09-28
Petschenka, G., Fei, C. S., Araya, J. J., Schröder, S., Timmermann, B. N., & Agrawal, A. A. (2018). Relative Selectivity of Plant Cardenolides for Na+/K+-ATPases From the Monarch Butterfly and Non-resistant Insects. Frontiers in plant science, 9, 1424. https://doi.org/10.3389/fpls.2018.01424
http://hdl.handle.net/1808/30951
10.3389/fpls.2018.01424
PMC6172315
A major prediction of coevolutionary theory is that plants may target particular herbivores with secondary compounds that are selectively defensive. The highly specialized monarch butterfly (Danaus plexippus) copes well with cardiac glycosides (inhibitors of animal Na+/K+-ATPases) from its milkweed host plants, but selective inhibition of its Na+/K+-ATPase by different compounds has not been previously tested. We applied 17 cardiac glycosides to the D. plexippus-Na+/K+-ATPase and to the more susceptible Na+/K+-ATPases of two non-adapted insects (Euploea core and Schistocerca gregaria). Structural features (e.g., sugar residues) predicted in vitro inhibitory activity and comparison of insect Na+/K+-ATPases revealed that the monarch has evolved a highly resistant enzyme overall. Nonetheless, we found evidence for relative selectivity of individual cardiac glycosides reaching from 4- to 94-fold differences of inhibition between non-adapted Na+/K+-ATPase and D. plexippus-Na+/K+-ATPase. This toxin receptor specificity suggests a mechanism how plants could target herbivores selectively and thus provides a strong basis for pairwise coevolutionary interactions between plants and herbivorous insects.
Copyright © 2018 Petschenka, Fei, Araya, Schröder, Timmermann and Agrawal.
Monarch butterfly
Na+/K+-ATPase
Cardenolide
Cardiac glycoside
Phytochemical diversity
Structure–activity relationship
Toxin–receptor interaction
Resistance
Relative Selectivity of Plant Cardenolides for Na+/K+-ATPases From the Monarch Butterfly and Non-resistant Insects
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/30951/1/Petschenka_2018.pdf
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oai:kuscholarworks.ku.edu:1808/308242020-11-11T09:01:03Zcom_1808_100col_1808_101
KU ScholarWorks
author
Brice-Tutt, Ariana C.
author
Senadheera, Sanjeewa N.
author
Ganno, Michelle L.
author
Eans, Shainnel O.
author
Khaliq, Tanvir
author
Murray, Thomas F.
author
McLaughlin, Jay P.
author
Aldrich, Jane V.
2020-11-10T21:59:16Z
2020-11-10T21:59:16Z
2020-09-02
Brice-Tutt, A. C., Senadheera, S. N., Ganno, M. L., Eans, S. O., Khaliq, T., Murray, T. F., McLaughlin, J. P., & Aldrich, J. V. (2020). Phenylalanine Stereoisomers of CJ-15,208 and [d-Trp]CJ-15,208 Exhibit Distinctly Different Opioid Activity Profiles. Molecules (Basel, Switzerland), 25(17), 3999. https://doi.org/10.3390/molecules25173999
http://hdl.handle.net/1808/30824
10.3390/molecules25173999
https://orcid.org/0000-0001-6107-2743https://orcid.org/0000-0003-0798-1721https://orcid.org/0000-0001-8521-4507https://orcid.org/0000-0001-9851-9342https://orcid.org/0000-0002-7954-9850
PMC7504817
The macrocyclic tetrapeptide cyclo[Phe-d-Pro-Phe-Trp] (CJ-15,208) and its stereoisomer cyclo[Phe-d-Pro-Phe-d-Trp] exhibit different opioid activity profiles in vivo. The present study evaluated the influence of the Phe residues’ stereochemistry on the peptides’ opioid activity. Five stereoisomers were synthesized by a combination of solid-phase peptide synthesis and cyclization in solution. The analogs were evaluated in vitro for opioid receptor affinity in radioligand competition binding assays, and for opioid activity and selectivity in vivo in the mouse 55 °C warm-water tail-withdrawal assay. Potential liabilities of locomotor impairment, respiratory depression, acute tolerance development, and place conditioning were also assessed in vivo. All of the stereoisomers exhibited antinociception following either intracerebroventricular or oral administration differentially mediated by multiple opioid receptors, with kappa opioid receptor (KOR) activity contributing for all of the peptides. However, unlike the parent peptides, KOR antagonism was exhibited by only one stereoisomer, while another isomer produced DOR antagonism. The stereoisomers of CJ-15,208 lacked significant respiratory effects, while the [d-Trp]CJ-15,208 stereoisomers did not elicit antinociceptive tolerance. Two isomers, cyclo[d-Phe-d-Pro-d-Phe-Trp] (3) and cyclo[Phe-d-Pro-d-Phe-d-Trp] (5), did not elicit either preference or aversion in a conditioned place preference assay. Collectively, these stereoisomers represent new lead compounds for further investigation in the development of safer opioid analgesics.
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Opioid peptide
Macrocyclic tetrapeptide
Multifunctional ligands
Structure-activity relationships
Kappa opioid receptor
Delta opioid receptor
Analgesics
Opioid liabilities
Phenylalanine Stereoisomers of CJ-15,208 and [d-Trp]CJ-15,208 Exhibit Distinctly Different Opioid Activity Profiles
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/30824/1/Brice-Tutt_2020.pdf
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Brice-Tutt_2020.pdf.txt
oai:kuscholarworks.ku.edu:1808/235922023-03-04T07:06:05Zcom_1808_100col_1808_101
KU ScholarWorks
author
Kokatla, Hari Prasad
author
Sil, Diptesh
author
Malladi, Subbalakshmi S.
author
Balakrishna, Rajalakshmi
author
Hermanson, Alec R.
author
Fox, Lauren M.
author
Wang, Xinkun
author
Dixit, Anshuman
author
David, Sunil A.
2017-04-06T17:08:20Z
2017-04-06T17:08:20Z
2013-09-12
Kokatla, H. P., Sil, D., Malladi, S. S., Balakrishna, R., Hermanson, A. R., Fox, L. M., … David, S. A. (2013). Exquisite Selectivity For Human Toll-like Receptor 8 in Substituted Furo[2,3-c]quinolines. Journal of Medicinal Chemistry, 56(17), 6871–6885. http://doi.org/10.1021/jm400694d
http://hdl.handle.net/1808/23592
10.1021/jm400694d
https://orcid.org/0000-0001-6457-0545
https://orcid.org/0000-0003-1377-0509
Toll-like receptor (TLR)-8 agonists activate adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds may be promising candidate adjuvants. We synthesized and evaluated hitherto unexplored furo[2,3-c]quinolines and its regioisomeric furo[3,2-c]quinolines, derived via a tandem, one-pot Sonogashira coupling and intramolecular 5 endo-dig cyclization strategy, in a panel of primary screens. We observed a pure TLR8 agonistic activity profile in select furo[2,3-c]quinolines, with maximal potency conferred by a C2-butyl group (EC50: 1.6 µM); shorter, longer, or substituted homologues, as well as compounds bearing C1 substitutions were inactive, which was rationalized by docking studies using the recently-described crystal structure of human TLR8. The best-in-class compound displayed prominent proinflammatory cytokine induction (including interleukin-12 and interleukin-18), but was bereft of interferon-α inducing properties, confirming its high selectivity for human TLR8.
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm400694d.
TLR8
TLR8 agonists
Vaccine adjuvants
Innate immunity
Furoquinolines
Sonogashira coupling
Exquisite Selectivity For Human Toll-like Receptor 8 in Substituted Furo[2,3-c]quinolines
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23592/1/Sil_2013.pdf
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Sil_2013.pdf.txt
oai:kuscholarworks.ku.edu:1808/237482018-12-27T16:21:53Zcom_1808_100col_1808_101
KU ScholarWorks
author
Samadi, Abbas K.
author
Bazzill, Joseph
author
Zhang, Xuan
author
Gallagher, Robert J.
author
Zhang, Huaping
author
Gollapudi, Rao
author
Kindscher, Kelly
author
Timmermann, Barbara N.
author
Cohen, Mark S.
2017-04-19T20:53:35Z
2017-04-19T20:53:35Z
2012-12
Samadi, Abbas K. et al. “Novel Withanolides Target Medullary Thyroid Cancer through Inhibition of Both RET Phosphorylation and the Mammalian Target of Rapamycin Pathway.” Surgery 152.6 (2012): 1238–1247.
http://hdl.handle.net/1808/23748
10.1016/j.surg.2012.08.031
Background
Despite development of current targeted therapies for medullary thyroid cancer (MTC), long-term survival remains unchanged. Recently isolated novel withanolide compounds from Solanaceae physalis are highly potent against MTCs. We hypothesize that these withanolides uniquely inhibit RET phosphorylation and the mammalian target of rapamycin (mTOR) pathway in MTC cells as a mechanism of antiproliferation and apoptosis.
Methods
MTC cells were treated with novel withanolides and MTC-targeted drugs. In vitro studies assessed cell viability and proliferation (MTS; trypan blue assays), apoptosis (flow cytometry with Annexin V/PI staining; confirmed by Western blot analysis), long-term cytotoxic effects (clonogenic assay), and suppression of key regulatory proteins such as RET, Akt, and mTOR (by Western blot analysis).
Results
The novel withanolides potently reduced MTC cell viability (half maximal inhibitory concentration [IC50], 270–2,850 nmol/L; 250–1,380 nmol/L for vandetanib; 360–1,640 nmol/L for cabozantinib) with induction of apoptosis at <1,000 nmol/L of drug. Unique from other targeted therapies, withanolides suppressed RET and Akt phosphorylation and protein expression (in a concentration- and time-dependent manner) as well as mTOR activity and translational activity of 4E-BP1 and protein synthesis mediated by p70S6kinase activation at IC50 concentrations.
Conclusion
Novel withanolides from Physalis selectively and potently inhibit MTC cells in vitro. Unlike other MTC-targeted therapies, these compounds uniquely inhibit both RET kinase activity and the Akt/mTOR prosurvival pathway. Further translational studies are warranted to evaluate their clinical potential.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Novel withanolides target medullary thyroid cancer through inhibition of both RET phosphorylation and the mammalian target of rapamycin pathway
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23748/1/timmerman_withanolides.pdf
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oai:kuscholarworks.ku.edu:1808/206252018-12-19T18:47:09Zcom_1808_100col_1808_101
KU ScholarWorks
author
Lu, Rongtao
author
Liu, Jianwei
author
Luo, Hongfu
author
Chikan, Viktor
author
Wu, Judy Z.
2016-04-01T19:08:27Z
2016-04-01T19:08:27Z
2016-01-18
Lu R, Liu J, Luo H, Chikan V, Wu JZ. Graphene/GaSe-Nanosheet Hybrid: Towards High Gain and Fast Photoresponse. Scientific Reports. 2016;6:19161. doi:10.1038/srep19161.
http://hdl.handle.net/1808/20625
10.1038/srep19161
Copyright © 2016, Macmillan Publishers Limited. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Graphene/GaSe-Nanosheet Hybrid: Towards High Gain and Fast Photoresponse
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/20625/1/Lu_2016.pdf
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oai:kuscholarworks.ku.edu:1808/240022019-04-12T14:16:16Zcom_1808_100col_1808_101
KU ScholarWorks
author
Koen, Yakov M.
author
Hajovsky, Heather
author
Liu, Ke
author
Williams, Todd D.
author
Galeva, Nadezhda A.
author
Staudinger, Jeffrey Leonard
author
Hanzlik, Robert P.
2017-05-08T16:29:47Z
2017-05-08T16:29:47Z
2012-08-20
Koen, Y. M., Hajovsky, H., Liu, K., Williams, T. D., Galeva, N. A., Staudinger, J. L., & Hanzlik, R. P. (2012). Liver Protein Targets of Hepatotoxic 4-Bromophenol Metabolites. Chemical Research in Toxicology, 25(8), 1777–1786. http://doi.org/10.1021/tx3002675
http://hdl.handle.net/1808/24002
10.1021/tx3002675
PMC3431021
The hepatotoxicity of bromobenzene (BB) is directly related to the covalent binding of both initially formed epoxide and secondary quinone metabolites to at least 45 different liver proteins. 4-Bromophenol (4BP) is a significant BB metabolite and a precursor to reactive quinone metabolites, yet when administered exogenously it has negligible hepatotoxicity compared to BB. The protein adducts of 4BP were thus labeled as non-toxic (Monks, T. J.; Hinson, J. A.; Gillette, J. R. (1982) Life Sci. 30, 841–848). To help identify which BB-derived adducts might be related to its cytotoxicity, we sought to identify the supposedly non-toxic adducts of 4BP and eliminate them from the BB target protein list. Administration of [14C]-4BP to phenobarbital-induced rats resulted in covalent binding of 0.25, 0.33 and 0.42 nmol-eq 4BP/mg protein in the mitochondrial, microsomal and cytosolic fractions, respectively. These values may be compared to published values of 3–6 nmol/mg protein from a comparable dose of [14C]-BB. After subcellular fractionation and 2D electrophoresis, 47 radioactive spots on 2D gels of the mitochondrial, microsomal and cytosolic fractions were excised, digested and analyzed by LC-MS/MS. Twenty nine of these spots contained apparently single proteins, of which 14 were non-redundant. Nine of the 14 are known BB targets. Incubating freshly-isolated rat hepatocytes with 4BP (0.1–0.5 mM) produced time- and concentration-dependent increases in lactate dehydrogenase release and changes in cellular morphology. LC-MS/MS analysis of the cell culture medium revealed rapid and extensive sulfation and glucuronidation of 4BP as well as formation of a quinone-derived glutathione conjugate. Studies with 7-hydroxycoumarin (7HC), (−)-borneol or D-(+)-galactosamine (DGN) showed that inhibiting the glucuronidation/sulfation of 4BP increased the formation of a GSH-bromoquinone adduct, increased covalent binding of 4BP to hepatocyte proteins and potentiated its cytotoxicity. Taken together, our data demonstrate that protein adduction by 4BP metabolites can be toxicologically consequential, and provide a mechanistic explanation for the failure of exogenously administered 4BP to cause hepatotoxicity. Thus the probable reason for the low toxicity of 4BP in vivo is that rapid conjugation limits its oxidation and covalent binding and thus its toxicity.
© 2012 American Chemical Society
Liver Protein Targets of Hepatotoxic 4-Bromophenol Metabolites
Article
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URL
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oai:kuscholarworks.ku.edu:1808/135372018-07-13T15:41:21Zcom_1808_100col_1808_101
KU ScholarWorks
author
Urban, Michael Joseph
author
Li, Chengyuan
author
Yu, Cuijuan
author
Lu, Yuanming
author
Krise, Joanna M.
author
McIntosh, Michelle P.
author
Rajewski, Roger A.
author
Blagg, Brian S. J.
author
Dobrowsky, Rick T.
2014-04-17T18:46:15Z
2014-04-17T18:46:15Z
2010-07-14
Urban, Michael J, Chengyuan Li, Cuijuan Yu, Yuanming Lu, Joanna M Krise, Michelle P McIntosh, Roger A Rajewski, Brian S J Blagg, and Rick T Dobrowsky. 2010. “Inhibiting Heat-Shock Protein 90 Reverses Sensory Hypoalgesia in Diabetic Mice.” ASN NEURO 2 (4). http://dx.doi.org/10.1042/AN20100015. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919983
http://hdl.handle.net/1808/13537
10.1042/AN20100015
Increasing the expression of Hsp70 (heat-shock protein 70) can inhibit sensory neuron degeneration after axotomy. Since the onset of DPN (diabetic peripheral neuropathy) is associated with the gradual decline of sensory neuron function, we evaluated whether increasing Hsp70 was sufficient to improve several indices of neuronal function. Hsp90 is the master regulator of the heat-shock response and its inhibition can up-regulate Hsp70. KU-32 (N-{7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy]-8-methyl-2-oxo-2H-chromen-3-yl}acetamide) was developed as a novel, novobiocin-based, C-terminal inhibitor of Hsp90 whose ability to increase Hsp70 expression is linked to the presence of an acetamide substitution of the prenylated benzamide moiety of novobiocin. KU-32 protected against glucose-induced death of embryonic DRG (dorsal root ganglia) neurons cultured for 3 days in vitro. Similarly, KU-32 significantly decreased neuregulin 1-induced degeneration of myelinated Schwann cell DRG neuron co-cultures prepared from WT (wild-type) mice. This protection was lost if the co-cultures were prepared from Hsp70.1 and Hsp70.3 KO (knockout) mice. KU-32 is readily bioavailable and was administered once a week for 6 weeks at a dose of 20 mg/kg to WT and Hsp70 KO mice that had been rendered diabetic with streptozotocin for 12 weeks. After 12 weeks of diabetes, both WT and Hsp70 KO mice developed deficits in NCV (nerve conduction velocity) and a sensory hypoalgesia. Although KU-32 did not improve glucose levels, HbA1c (glycated haemoglobin) or insulin levels, it reversed the NCV and sensory deficits in WT but not Hsp70 KO mice. These studies provide the first evidence that targeting molecular chaperones reverses the sensory hypoalgesia associated with DPN.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited
Diabetic neuropathy
Dorsal Root Ganglia Neuron
Heat-shock protein 70
Molecular Chaperone
Nerve conduction velocity
Neurodegeneration
Inhibiting heat-shock protein 90 reverses sensory hypoalgesia in diabetic mice
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/13537/3/Urban_2010.pdf
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oai:kuscholarworks.ku.edu:1808/259392018-12-14T16:20:34Zcom_1808_100col_1808_101
KU ScholarWorks
author
Khandelwal, Anuj
author
Kent, Caitlin N.
author
Balch, Maurie
author
Peng, Shuxia
author
Mishra, Sanket J.
author
Deng, Junpeng
author
Day, Victor W.
author
Liu, Weiya
author
Subramanian, Chitra
author
Cohen, Mark S.
author
Holzbeierlein, Jeffery M.
author
Matts, Robert L.
author
Blagg, Brian S. J.
2018-02-08T18:48:43Z
2018-02-08T18:48:43Z
2018-01-30
Khandelwal, A., Kent, C. N., Balch, M., Peng, S., Mishra, S. J., Deng, J., ... & Holzbeierlein, J. M. (2018). Structure-guided design of an Hsp90β N-terminal isoform-selective inhibitor. Nature communications, 9(1), 425.
http://hdl.handle.net/1808/25939
10.1038/s41467-017-02013-1
https://orcid.org/0000-0003-4492-4400
PMC5789826
The 90 kDa heat shock protein (Hsp90) is a molecular chaperone responsible for folding proteins that are directly associated with cancer progression. Consequently, inhibition of the Hsp90 protein folding machinery results in a combinatorial attack on numerous oncogenic pathways. Seventeen small-molecule inhibitors of Hsp90 have entered clinical trials, all of which bind the Hsp90 N-terminus and exhibit pan-inhibitory activity against all four Hsp90 isoforms. pan-Inhibition of Hsp90 appears to be detrimental as toxicities have been reported alongside induction of the pro-survival heat shock response. The development of Hsp90 isoform-selective inhibitors represents an alternative approach towards the treatment of cancer that may limit some of the detriments. Described herein is a structure-based approach to design isoform-selective inhibitors of Hsp90β, which induces the degradation of select Hsp90 clients without concomitant induction of Hsp90 levels. Together, these initial studies support the development of Hsp90β-selective inhibitors as a method to overcome the detriments associated with pan-inhibition.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Structure-guided design of an Hsp90â N-terminal isoform-selective inhibitor
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/25939/1/Khandelwal_2018.pdf
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oai:kuscholarworks.ku.edu:1808/240752019-04-12T14:16:57Zcom_1808_100col_1808_101
KU ScholarWorks
author
Peterson, Laura B.
author
Eskew, Jeffrey D.
author
Vielhauer, George A.
author
Blagg, Brian S. J.
2017-05-10T17:57:24Z
2017-05-10T17:57:24Z
2012-06-04
Peterson, L. B., Eskew, J. D., Vielhauer, G. A., & Blagg, B. S. J. (2012). The hERG channel is dependent upon the Hsp90α isoform for maturation and trafficking. Molecular Pharmaceutics, 9(6), 1841–1846. http://doi.org/10.1021/mp300138n
http://hdl.handle.net/1808/24075
10.1021/mp300138n
PMC3557513
Heat shock protein 90 (Hsp90) has emerged as a promising therapeutic target for the treatment of cancer. Several Hsp90 inhibitors have entered clinical trials. However, some toxicological detriments have arisen, such as cardiotoxicity resulting from hERG inhibition following the administration of Hsp90 inhibitors. We sought to investigate this toxicity as hERG has been previously reported as a client protein that depends upon Hsp90 for its maturation and functional trafficking. In this study we show that hERG depends upon a single Hsp90 isoform. hERG preferentially co-immunoprecipitated with Hsp90α and genetic knockdown of Hsp90α, but not Hsp90β, resulted in a trafficking-defective hERG channel. This study demonstrates the importance of delineating the isoform dependence of Hsp90 client proteins and provides rationale for the design of isoform-selective Hsp90 inhibitors that avoid detrimental effects
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Molecular Pharmaceutics, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/mp300138n
Hsp90
Isoform
hERG
The hERG channel is dependent upon the Hsp90α isoform for maturation and trafficking
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/24075/1/Peterson_2012.pdf
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oai:kuscholarworks.ku.edu:1808/127632018-11-30T16:21:15Zcom_1808_100col_1808_101
KU ScholarWorks
author
Eskew, Jeffrey D.
author
Sadikot, Takrima
author
Morales, Pedro
author
Duren, Alicia
author
Dunwiddie, Irene
author
Swink, Megan
author
Zhang, Xiaoying
author
Hembruff, Stacey
author
Donnelly, Alison C.
author
Rajewski, Roger A.
author
Blagg, Brian S. J.
2014-01-17T17:48:34Z
2014-01-17T17:48:34Z
2011-10-31
Eskew, Jeffery D, Takrima Sadikot, Pedro Morales, Alicia Duren, Irene Dunwiddie, Megan Swink, Xiaoying Zhang, et al. 2011. “Development and Characterization of a Novel C-Terminal Inhibitor of Hsp90 in Androgen Dependent and Independent Prostate Cancer Cells.” BMC Cancer 11 (1) : 468. http://dx.doi.org/10.1186/1471-2407-11-468.
http://hdl.handle.net/1808/12763
10.1186/1471-2407-11-468
Background: The molecular chaperone, heat shock protein 90 (Hsp90) has been shown to be overexpressed in a
number of cancers, including prostate cancer, making it an important target for drug discovery. Unfortunately,
results with N-terminal inhibitors from initial clinical trials have been disappointing, as toxicity and resistance
resulting from induction of the heat shock response (HSR) has led to both scheduling and administration concerns.
Therefore, Hsp90 inhibitors that do not induce the heat shock response represent a promising new direction for
the treatment of prostate cancer. Herein, the development of a C-terminal Hsp90 inhibitor, KU174, is described,
which demonstrates anti-cancer activity in prostate cancer cells in the absence of a HSR and describe a novel
approach to characterize Hsp90 inhibition in cancer cells.
Methods: PC3-MM2 and LNCaP-LN3 cells were used in both direct and indirect in vitro Hsp90 inhibition assays
(DARTS, Surface Plasmon Resonance, co-immunoprecipitation, luciferase, Western blot, anti-proliferative, cytotoxicity
and size exclusion chromatography) to characterize the effects of KU174 in prostate cancer cells. Pilot in vivo
efficacy studies were also conducted with KU174 in PC3-MM2 xenograft studies.
Results: KU174 exhibits robust anti-proliferative and cytotoxic activity along with client protein degradation and
disruption of Hsp90 native complexes without induction of a HSR. Furthermore, KU174 demonstrates direct binding
to the Hsp90 protein and Hsp90 complexes in cancer cells. In addition, in pilot in-vivo proof-of-concept studies
KU174 demonstrates efficacy at 75 mg/kg in a PC3-MM2 rat tumor model.
Conclusions: Overall, these findings suggest C-terminal Hsp90 inhibitors have potential as therapeutic agents for
the treatment of prostate cancer.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Hsp90
Prostate cancer
Novobiocin
C-terminal inhibitors
N-terminal inhibitors
Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/12763/1/Eskew_2011.pdf
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oai:kuscholarworks.ku.edu:1808/83162019-04-12T14:43:20Zcom_1808_8219com_1808_100col_1808_8220col_1808_101
KU ScholarWorks
author
Hanzlik, Robert P.
author
Michaely, William J.
2011-10-31T16:10:12Z
2011-10-31T16:10:12Z
1975
R. P. Hanzlik and W. J. Michaely, "Metal-Catalyzed Hydration of 2-Pyridyloxirane," J. C. S. Chem. Comm.,113-114 (1975). http://dx.doi.org/10.1039/C39750000113
http://hdl.handle.net/1808/8316
10.1039/C39750000113
In the presence of CuII the hydration of 2-pyridyloxiran is accelerated 18,000-fold, and its reaction with Cl–, Br–, and MeO– becomes 100% regiospecific for β-attack.
en
Metal-Catalyzed Hydration of 2-Pyridyloxirane
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/8316/1/c39750000113.pdf
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oai:kuscholarworks.ku.edu:1808/323562022-01-07T09:01:00Zcom_1808_100col_1808_101
KU ScholarWorks
author
Liu, Lei
author
Lauro, Bianca M.
author
Wolfe, Michael S.
author
Selkoe, Dennis J.
2022-01-06T19:34:57Z
2022-01-06T19:34:57Z
2021-02-08
Liu, L., Lauro, B. M., Wolfe, M. S., & Selkoe, D. J. (2021). Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. The Journal of biological chemistry, 296, 100393. https://doi.org/10.1016/j.jbc.2021.100393
http://hdl.handle.net/1808/32356
10.1016/j.jbc.2021.100393
https://orcid.org/ 0000-0002-4604-4629https://orcid.org/ 0000-0002-5721-9092
PMC7961089
γ-Secretase is responsible for the proteolysis of amyloid precursor protein (APP) into amyloid-beta (Aβ) peptides, which are centrally implicated in the pathogenesis of Alzheimer’s disease (AD). The biochemical mechanism of how processing by γ-secretase is regulated, especially as regards the interaction between enzyme and substrate, remains largely unknown. Here, mutagenesis reveals that the hydrophilic loop-1 (HL-1) of presenilin-1 (PS1) is critical for both γ-secretase step-wise cleavages (processivity) and its allosteric modulation by heterocyclic γ-modulatory compounds. Systematic mutagenesis of HL-1, including all of its familial AD mutations and additional engineered variants, and quantification of the resultant Aβ products show that HL-1 is necessary for proper sequential γ-secretase processivity. We identify Y106, L113, and Y115 in HL-1 as key targets for heterocyclic γ-secretase modulators (GSMs) to stimulate processing of pathogenic Aβ peptides. Further, we confirm that the GxxxG domain in the APP transmembrane region functions as a critical substrate motif for γ-secretase processivity: a G29A substitution in APP-C99 mimics the beneficial effects of GSMs. Together, these findings provide a molecular basis for the structural regulation of γ-processivity by enzyme and substrate, facilitating the rational design of new GSMs that lower AD-initiating amyloidogenic Aβ peptides.
© 2021 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license.
γ-secretase
Aβ
Presenilin-1
γ-secretase modulator
Alzheimer’s disease
Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides
Article
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URL
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oai:kuscholarworks.ku.edu:1808/237182018-11-15T17:06:26Zcom_1808_100col_1808_101
KU ScholarWorks
author
Li, Guodong
author
Lin, Wenwei
author
Araya, Juan Jose
author
Chen, Taosheng
author
Timmermann, Barbara N.
author
Guo, Grace L.
2017-04-17T20:36:49Z
2017-04-17T20:36:49Z
2012-12-04
Li, Guodong et al. “A Tea Catechin, Epigallocatechin-3-Gallate, Is a Unique Modulator of the Farnesoid X Receptor.” Toxicology and Applied Pharmacology 258.2 (2012): 268–274.
http://hdl.handle.net/1808/23718
10.1016/j.taap.2011.11.006
https://orcid.org/0000-0003-4525-7291
Farnesoid X receptor (FXR) is a ligand-activated nuclear receptor and serves as a key regulator to maintain health of the liver and intestine. Bile acids are endogenous ligands of FXR, and there are increasing efforts to identify FXR modulators to serve as biological probes and/or pharmaceutical agents. Natural FXR ligands isolated from plants may serve as models to synthesize novel FXR modulators. In this study, we demonstrated that epigallocatechin-3-gallate (EGCG), a major tea catechin, specifically and dose-dependently activates FXR. In addition, EGCG induced FXR target gene expression in vitro. Surprisingly, in a co-activator (SRC2) recruitment assay, we found that EGCG does not recruit SRC2 to FXR, but it dose-dependently inhibits recruitment of SRC2 to FXR (IC50, 1 μM) by GW6064, which is a potent FXR synthetic ligand. In addition, EGCG suppressed FXR target gene expression induced by either GW4064 or chenodeoxycholic acid in vitro. Furthermore, wild-type and FXR knockout mice treated with an acute dose of EGCG had induced mRNA expression in a subset of FXR target genes in the intestine but not in the liver. In conclusion, EGCG is a unique modulator of FXR in the intestine and may serve as an important model for future development of FXR modulators.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Farnesoid x receptor
Epigallocatechin-3-gallate
Nuclear receptor
Tea catechin
Modulator
Mice
A tea catechin, epigallocatechin-3-gallate, is a unique modulator of the farnesoid X receptor
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23718/1/timmerman_tea.pdf
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oai:kuscholarworks.ku.edu:1808/305052020-06-16T08:01:08Zcom_1808_100col_1808_101
KU ScholarWorks
author
Cassell, Robert J.
author
Sharma, Krishna K.
author
Su, Hongyu
author
Cummins, Benjamin R.
author
Cui, Haoyue
author
Mores, Kendall L.
author
Blaine, Arryn T.
author
Altman, Ryan A.
author
Rijn, Richard M. van
2020-06-15T21:09:32Z
2020-06-15T21:09:32Z
2019-12-12
Cassell, R. J., Sharma, K. K., Su, H., Cummins, B. R., Cui, H., Mores, K. L., Blaine, A. T., Altman, R. A., & van Rijn, R. M. (2019). The Meta-Position of Phe4 in Leu-Enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors. Molecules (Basel, Switzerland), 24(24), 4542. https://doi.org/10.3390/molecules24244542
http://hdl.handle.net/1808/30505
10.3390/molecules24244542
https://orcid.org/0000-0003-4927-745Xhttps://orcid.org/0000-0002-8724-1098https://orcid.org/0000-0002-9957-1633
PMC6943441
As tool compounds to study cardiac ischemia, the endogenous δ-opioid receptors (δOR) agonist Leu5-enkephalin and the more metabolically stable synthetic peptide (d-Ala2, d-Leu5)-enkephalin are frequently employed. However, both peptides have similar pharmacological profiles that restrict detailed investigation of the cellular mechanism of the δOR’s protective role during ischemic events. Thus, a need remains for δOR peptides with improved selectivity and unique signaling properties for investigating the specific roles for δOR signaling in cardiac ischemia. To this end, we explored substitution at the Phe4 position of Leu5-enkephalin for its ability to modulate receptor function and selectivity. Peptides were assessed for their affinity to bind to δORs and µ-opioid receptors (µORs) and potency to inhibit cAMP signaling and to recruit β-arrestin 2. Additionally, peptide stability was measured in rat plasma. Substitution of the meta-position of Phe4 of Leu5-enkephalin provided high-affinity ligands with varying levels of selectivity and bias at both the δOR and µOR and improved peptide stability, while substitution with picoline derivatives produced lower-affinity ligands with G protein biases at both receptors. Overall, these favorable substitutions at the meta-position of Phe4 may be combined with other modifications to Leu5-enkephalin to deliver improved agonists with finely tuned potency, selectivity, bias and drug-like properties.
© 2019 by the authors.
Leu-enkephalin
Beta-arrestin
Mu opioid receptor
Delta opioid receptor
Biased signaling
DADLE
Ischemia
Plasma stability
The Meta-Position of Phe4 in Leu-Enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/30505/1/Cassell_2019.pdf
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oai:kuscholarworks.ku.edu:1808/309642020-12-15T09:00:46Zcom_1808_100col_1808_101
KU ScholarWorks
author
Rodnin, Mykola V.
author
Kashipathy, Maithri M.
author
Kyrychenko, Alexander
author
Battaile, Kevin P.
author
Lovell, Scott
author
Ladokhin, Alexey S.
2020-12-14T20:27:19Z
2020-12-14T20:27:19Z
2020-11-07
Rodnin, M. V., Kashipathy, M. M., Kyrychenko, A., Battaile, K. P., Lovell, S., & Ladokhin, A. S. (2020). Structure of the Diphtheria Toxin at Acidic pH: Implications for the Conformational Switching of the Translocation Domain. Toxins, 12(11), 704. https://doi.org/10.3390/toxins12110704
http://hdl.handle.net/1808/30964
10.3390/toxins12110704
https://orcid.org/0000-0002-6223-0990
PMC7695028
Diphtheria toxin, an exotoxin secreted by Corynebacterium that causes disease in humans by inhibiting protein synthesis, enters the cell via receptor-mediated endocytosis. The subsequent endosomal acidification triggers a series of conformational changes, resulting in the refolding and membrane insertion of the translocation (T-)domain and ultimately leading to the translocation of the catalytic domain into the cytoplasm. Here, we use X-ray crystallography along with circular dichroism and fluorescence spectroscopy to gain insight into the mechanism of the early stages of pH-dependent conformational transition. For the first time, we present the high-resolution structure of the diphtheria toxin at a mildly acidic pH (5–6) and compare it to the structure at neutral pH (7). We demonstrate that neither catalytic nor receptor-binding domains change their structure upon this acidification, while the T-domain undergoes a conformational change that results in the unfolding of the TH2–3 helices. Surprisingly, the TH1 helix maintains its conformation in the crystal of the full-length toxin even at pH 5. This contrasts with the evidence from the new and previously published data, obtained by spectroscopic measurements and molecular dynamics computer simulations, which indicate the refolding of TH1 upon the acidification of the isolated T-domain. The overall results imply that the membrane interactions of the T-domain are critical in ensuring the proper conformational changes required for the preparation of the diphtheria toxin for the cellular entry.
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Diphtheria toxin structure
X-ray crystallography
Helix unfolding
Acidification
Conformational switching
Structure of the Diphtheria Toxin at Acidic pH: Implications for the Conformational Switching of the Translocation Domain
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/30964/1/Rodnin_2020.pdf
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oai:kuscholarworks.ku.edu:1808/342632023-06-02T06:05:53Zcom_1808_100col_1808_101
KU ScholarWorks
author
Shinde, Anand H.
author
Thomas, Annu Anna
author
Mague, Joel T.
author
Sathyamoorthi, Shyam
2023-06-01T14:46:32Z
2023-06-01T14:46:32Z
2021-10-19
Shinde, A. H., Thomas, A. A., Mague, J. T., & Sathyamoorthi, S. (2021). Highly Regio- and Diastereoselective Tethered Aza-Wacker Cyclizations of Alkenyl Phosphoramidates. The Journal of organic chemistry, 86(21), 14732–14758. https://doi.org/10.1021/acs.joc.1c01483
https://hdl.handle.net/1808/34263
10.1021/acs.joc.1c01483
https://orcid.org/0000-0003-1966-8505https://orcid.org/0000-0003-4705-7349
PMC10119688
We present highly diastereoselective tethered aza-Wacker cyclization reactions of alkenyl phosphoramidates. “Arming” the phosphoramidate tether with 5-chloro-8-quinolinol was essential to achieving >20:1 diastereoselectivity in these reactions. The substrate scope with respect to alkenyl alcohols and phosphoramidate tether was extensively explored. The scalability of the oxidative cyclization was demonstrated, and the product cyclophosphoramidates were shown to be valuable synthons, including for tether removal. With chiral alkenyl precursors, enantiopure cyclic phosphoramidates were formed.
© 2021 American Chemical Society
Highly Regio- and Diastereoselective Tethered Aza-Wacker Cyclizations of Alkenyl Phosphoramidates
Article
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URL
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oai:kuscholarworks.ku.edu:1808/238992018-07-17T15:42:43Zcom_1808_100col_1808_101
KU ScholarWorks
author
Mays, Jared R.
author
Hill, Stephanie A.
author
Moyers, Justin T.
author
Blagg, Brian S. J.
2017-05-04T20:00:49Z
2017-05-04T20:00:49Z
2010-01-01
Mays, J. R., Hill, S. A., Moyers, J. T., & Blagg, B. S. J. (2010). The Synthesis and Evaluation of Flavone and Isoflavone Chimeras of Novobiocin and Derrubone. Bioorganic & Medicinal Chemistry, 18(1), 249. http://doi.org/10.1016/j.bmc.2009.10.061
http://hdl.handle.net/1808/23899
10.1016/j.bmc.2009.10.061
PMC2818389
The natural products novobiocin and derrubone have both demonstrated Hsp90 inhibition and structure–activity relationships have been established for each scaffold. Given these compounds share several key structural features, we hypothesized that incorporation of elements from each could provide insight to structural features important for Hsp90 inhibition. Thus, chimeric analogues of novobiocin and derrubone were constructed and evaluated. These studies confirmed that the functionality present at the 3-position of the isoflavone plays a critical role in determining Hsp90 inhibition and suggests that the bicyclic ring system present in both novobiocin and derrubone do not share similar modes of binding.
This article is made available under an Attribution-NonCommercial-NoDerivs 3.0 United States (CC BY-NC-ND 3.0 US) License.
Hsp90
Novobiocin
Derrubone
Anticancer
The Synthesis and Evaluation of Flavone and Isoflavone Chimeras of Novobiocin and Derrubone
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23899/1/Mays_Elsevier_2010.pdf
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URL
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oai:kuscholarworks.ku.edu:1808/238952018-07-17T15:41:48Zcom_1808_100col_1808_101
KU ScholarWorks
author
Hutt, Oliver E.
author
Inagaki, Jun
author
Reddy, Bollu S.
author
Nair, Sajiv K.
author
Reiff, Emily A.
author
Henri, John T.
author
Greiner, Jack F.
author
VanderVelde, David G.
author
Chiu, Ting-Lan
author
Amin, Elizabeth A.
author
Himes, Richard H.
author
Georg, Gunda I.
2017-05-04T19:10:31Z
2017-05-04T19:10:31Z
2009-06-15
Hutt, O. E., Inagaki, J., Reddy, B. S., Nair, S. K., Reiff, E. A., Henri, J. T., … Georg, G. I. (2009). Total synthesis and evaluation of 22-(3-azidobenzoyloxy)methyl epothilone C for photoaffinity labeling of β-tubulin. Bioorganic & Medicinal Chemistry Letters, 19(12), 3293–3296. http://doi.org/10.1016/j.bmcl.2009.04.077
http://hdl.handle.net/1808/23895
10.1016/j.bmcl.2009.04.077
PMC2803616
The total synthesis of 22-(3-azidobenzoyloxy)methyl epothilone C is described as a potential photoaffinity probe to elucidate the β-tubulin binding site. A sequential Suzuki-aldol-Yamaguchi macrolactonization strategy was utilized employing a novel derivatized C1–C6 fragment. The C22-functionalized analog exhibited good activity in microtubule assembly assays, but cytotoxicity was significantly reduced. Molecular modeling simulations indicated that excessive steric bulk in the C22 position is accommodated by the large hydrophobic pocket of the binding site. Photoaffinity labeling studies were inconclusive suggesting non-specific labeling.
This article is made available under an Attribution-NonCommercial-NoDerivs 3.0 United States (CC BY-NC-ND 3.0 US) License.
Epothilone
Photoaffinity labels
Microtubules
Total synthesis and evaluation of 22-(3-azidobenzoyloxy)methyl epothilone C for photoaffinity labeling of β-tubulin
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23895/1/Hutt_Elsevier_2009.pdf
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oai:kuscholarworks.ku.edu:1808/240322018-07-17T15:44:47Zcom_1808_100col_1808_101
KU ScholarWorks
author
Franklin, Jade M.
author
Vasiljevik, Tamara
author
Prisinzano, Thomas E.
author
Carrasco, Gonzalo A.
2017-05-08T20:48:34Z
2017-05-08T20:48:34Z
2012-11-19
Franklin, Jade M. et al. “Cannabinoid Agonists Increase the Interaction between Β-Arrestin 2 and ERK1/2 and Upregulate Β-Arrestin 2 and 5-HT2A Receptors.” Pharmacological research : the official journal of the Italian Pharmacological Society 68.1 (2013): 46–58.
http://hdl.handle.net/1808/24032
10.1016/j.phrs.2012.11.002
PMC3562593
We have recently reported that selective cannabinoid 2 (CB2) receptor agonists upregulate 5-HT2A receptors by enhancing ERK1/2 signaling in prefrontal cortex (PFCx). Increased activity of cortical 5-HT2A receptors has been associated with several neuropsychiatric disorders such as anxiety and schizophrenia. Here we examine the mechanisms involved in this enhanced ERK1/2 activation in rat PFCx and in a neuronal cell model. Sprague-Dawley rats treated with a non-selective cannabinoid agonist (CP55940, 50 μg/kg, 7 days, i.p.) showed enhanced co-immunoprecipitation of β-Arrestin 2 and ERK1/2, enhanced pERK protein levels, and enhanced expression of β-Arrestin 2 mRNA and protein levels in PFCx. In a neuronal cell line, we found that selective CB2 receptor agonists upregulate β-Arrestin 2, an effect that was prevented by selective CB2 receptor antagonist JTE-907 and CB2 shRNA lentiviral particles. Additionally, inhibition of clathrin-mediated endocytosis, ERK1/2, and the AP-1 transcription factor also prevented the cannabinoid receptor-induced upregulation of β-Arrestin 2. Our results suggest that sustained activation of CB2 receptors would enhance β-Arrestin 2 expression possibly contributing to its increased interaction with ERK1/2 thereby driving the upregulation of 5-HT2A receptors. The CB2 receptor-mediated upregulation of β-Arrestin 2 would be mediated, at least in part, by an ERK1/2-dependent activation of AP-1. These data could provide the rationale for some of the adverse effects associated with repeated cannabinoid exposure and shed light on some CB2 receptor agonists that could represent an alternative therapeutic because of their minimal effect on serotonergic neurotransmission.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Cannabinoid receptors
5-HT2A receptor
ERK1/2
β-Arrestin 2
Prefrontal cortex
Cannabinoid Agonists Increase the Interaction between β-Arrestin 2 and ERK1/2 and Upregulate β-Arrestin 2 and 5-HT2A Receptors
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/24032/1/prisinzano_agonists.pdf
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URL
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oai:kuscholarworks.ku.edu:1808/267262018-12-06T18:29:40Zcom_1808_100col_1808_101
KU ScholarWorks
author
Joshi, Anand Anant
author
Murray, Thomas F.
author
Aldrich, Jane V.
2018-09-14T18:15:27Z
2018-09-14T18:15:27Z
2017-05-02
Anand A. Joshi, Thomas F. Murray, Jane V. Aldrich
Biopolymers. 2017 Sep; 108(5): 10.1002/bip.23026. doi: 10.1002/bip.23026
http://hdl.handle.net/1808/26726
https://doi.org/10.1002/bip.23026
PMC6003702
To date structure-activity relationship (SAR) studies of the dynorphins (Dyn), endogenous peptides for kappa opioid receptors (KOR), have focused almost exclusively on Dyn A with minimal studies on Dyn B. While both Dyn A and Dyn B have identical N-terminal sequences, their C-terminal sequences differ which could result in differences in pharmacological activity. We performed an alanine scan of the non-glycine residues up through residue 11 of Dyn B amide to explore the role of these side chains in the activity of Dyn B. The analogs were synthesized by fluorenylmethyloxycarbonyl (Fmoc)-based solid phase peptide synthesis and evaluated for their opioid receptor affinities and opioid potency and efficacy at KOR. Similar to Dyn A the N-terminal Tyr1 and Phe4 residues of Dyn B amide are critical for opioid receptor affinity and KOR agonist potency. The basic residues Arg6 and Arg7 contribute to the KOR affinity and agonist potency of Dyn B amide, while Lys10 contributes to the opioid receptor affinity, but not KOR agonist potency, of this peptide. Comparison to the Ala analogs of Dyn A(1-13) suggests that the basic residues in the C-terminus of both peptides contribute to KOR binding, but differences in their relative positions may contribute to the different pharmacological profiles of Dyn A and Dyn B. The other unique C-terminal residues in Dyn B amide also appear to influence the relative affinity of this peptide for KOR. This SAR information may be applied in the design of new Dyn B analogs that could be useful pharmacological tools
Dynorphin B
Alanine scan
Kappa opioid receptor
Structure-activity relationships
C-terminal basic residues
Alanine scan of the opioid peptide dynorphin B amide
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/26726/1/Joshi_2017_AlanineScan.pdf
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oai:kuscholarworks.ku.edu:1808/235822019-04-12T14:12:37Zcom_1808_100col_1808_101
KU ScholarWorks
author
Prisinzano, Thomas E.
2017-04-06T16:10:53Z
2017-04-06T16:10:53Z
2013-05-09
Prisinzano, T. E. (2013). 2012 David W. Robertson Award for Excellence in Medicinal Chemistry: Neoclerodanes as Atypical Opioid Receptor Ligands. Journal of Medicinal Chemistry, 56(9), 3435–3443. http://doi.org/10.1021/jm400388u
http://hdl.handle.net/1808/23582
10.1021/jm400388u
The neoclerodane diterpene salvinorin A is the major active component of the hallucinogenic mint plant Salvia divinorum Epling & Játiva (Lamiaceae). Since the finding that salvinorin A exerts its potent psychotropic actions through the activation of opioid receptors, the site of action of morphine and related analogues, there has been much interest in elucidating the underlying mechanisms behind its effects. These effects are particularly remarkable, because (1) salvinorin A is the first reported non-nitrogenous opioid receptor agonist, and (2) its effects are not mediated through the previously investigated targets of psychotomimetics. This perspective outlines our research program, illustrating a new direction to the development of tools to further elucidate the biological mechanisms of drug tolerance and dependence. The information gained from these efforts is expected to facilitate the design of novel agents to treat pain, drug abuse, and other CNS disorders.
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm900254k.
Opioids
Salvinorin A.
Salvia divinorum
Herkinorin
Neoclerodanes
2012 David W. Robertson Award for Excellence in Medicinal Chemistry: Neoclerodanes as Atypical Opioid Receptor Ligands
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23582/1/Prisinzano_2013.pdf
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URL
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oai:kuscholarworks.ku.edu:1808/233652018-07-17T15:13:18Zcom_1808_100col_1808_101
KU ScholarWorks
author
Johnson, Matthew W.
author
MacLean, Katherine A.
author
Reissig, Chad J.
author
Prisinzano, Thomas E.
author
Griffiths, Roland R.
2017-03-08T20:05:19Z
2017-03-08T20:05:19Z
2012-05-01
Johnson, Matthew W., Katherine A. Maclean, Chad J. Reissig, Thomas E. Prisinzano, and Roland R. Griffiths. "Human Psychopharmacology and Dose-effects of Salvinorin A, a Kappa Opioid Agonist Hallucinogen Present in the Plant Salvia Divinorum." Drug and Alcohol Dependence 115.1-2 (2011): 150-55.
http://hdl.handle.net/1808/23365
10.1016/j.drugalcdep.2010.11.005
Salvinorin A is a potent, selective nonnitrogenous kappa opioid agonist and the known psychoactive constituent of Salvia divinorum, a member of the mint family that has been used for centuries by Mazatec shamans of Mexico for divination and spiritual healing. Salvia divinorum has over the last several years gained increased popularity as a recreational drug. This is a double-blind, placebo controlled study of salvinorin A in 4 psychologically and physically healthy hallucinogen-using adults. Across sessions, participants inhaled 16 ascending doses of salvinorin A and 4 intermixed placebo doses under comfortable and supportive conditions. Doses ranged from 0.375 μg/kg to 21 μg/kg. Subject-rated drug strength was assessed every 2 minutes for 60 minutes after inhalation. Orderly time- and dose-related effects were observed. Drug strength ratings peaked at 2 minutes (first time point) and definite subjective effects were no longer present at approximately 20 minutes after inhalation. Dose-related increases were observed on questionnaire measures of mystical-type experience (Mysticism Scale) and subjective effects associated with classic serotonergic (5-HT2A) hallucinogens (Hallucinogen Rating Scale). Salvinorin A did not significantly increase heart rate or blood pressure. Participant narratives indicated intense experiences characterized by disruptions in vestibular and interoceptive signals (e.g., change in spatial orientation, pressure on the body) and unusual and sometimes recurring themes across sessions such as revisiting childhood memories, cartoon-like imagery, and contact with entities. Under these prepared and supportive conditions, salvinorin A occasioned a unique profile of subjective effects having similarities to classic hallucinogens, including mystical-type effects.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Salvinorin A
Salvia divinorum
Kappa opiod agonist
Hallucinogen
Psychedelic
Humans
Human psychopharmacology and dose-effects of salvinorin A, a kappa-opioid agonist hallucinogen present in the plant Salvia divinorum
Article
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oai:kuscholarworks.ku.edu:1808/134172018-11-20T22:28:15Zcom_1808_8219com_1808_100col_1808_8220col_1808_101
KU ScholarWorks
author
Hong, Lin
author
Kenney, S. Ray
author
Phillips, Genevieve K.
author
Smipson, Denise
author
Schroeder, Chad E.
author
Nöth, Julica
author
Romero, Elsa
author
Swanson, Scarlett
author
Waller, Anna
author
Strouse, J. Jacob
author
Carter, Mark B.
author
Chigaev, Alexandre
author
Ursu, Oleg
author
Opera, Tudor
author
Hjulle, Brian
author
Golden, Jennifer E.
author
Aubé, Jeffrey
author
Hudson, Laurie G.
author
Buranda, Tione
author
Sklar, Larry A.
author
Wandinger-Ness, Angela
2014-04-08T14:24:04Z
2014-04-08T14:24:04Z
2013-02-04
Hong, Lin; Kenney, S. Ray; K. Phillips, Genevieve; Simpson, Denise; E. Schroeder, Chad; Nöth, Julica; Romero, Elsa; Swanson, Scarlett; Waller, Anna; Strouse, J. Jacob; Carter, Mark; Chigaev, Alexandre; Ursu, Oleg; Oprea, Tudor; Hjelle, Brian; E. Golden, Jennifer; Aubé, Jeffrey; Hudson, Laurie G.; Buranda, Tione; Sklar, Larry A.; & Wandinger-Ness, Angela; 2013 “Characterization of a Cdc42 Protein Inhibitor and Its Use as a Molecular Probe” J. Biol. Chem. 288:8531-8543 http://dx.doi.org/10.1074/jbc.M112.435941
http://hdl.handle.net/1808/13417
10.1074/jbc.M112.435941
https://orcid.org/0000-0003-1049-5767https://orcid.org/0000-0002-6813-3710
Cdc42 plays important roles in cytoskeleton organization, cell cycle progression, signal transduction, and vesicle trafficking. Overactive Cdc42 has been implicated in the pathology of cancers, immune diseases, and neuronal disorders. Therefore, Cdc42 inhibitors would be useful in probing molecular pathways and could have therapeutic potential. Previous inhibitors have lacked selectivity and trended toward toxicity. We report here the characterization of a Cdc42-selective guanine nucleotide binding lead inhibitor that was identified by high throughput screening. A second active analog was identified via structure-activity relationship studies. The compounds demonstrated excellent selectivity with no inhibition toward Rho and Rac in the same GTPase family. Biochemical characterization showed that the compounds act as noncompetitive allosteric inhibitors. When tested in cellular assays, the lead compound inhibited Cdc42-related filopodia formation and cell migration. The lead compound was also used to clarify the involvement of Cdc42 in the Sin Nombre virus internalization and the signaling pathway of integrin VLA-4. Together, these data present the characterization of a novel Cdc42-selective allosteric inhibitor and a related analog, the use of which will facilitate drug development targeting Cdc42-related diseases and molecular pathway studies that involve GTPases.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License .
Cdc42
Cytoskeleton
Gtpase
Intergin
Migration
Characterization of a Cdc42 Protein Inhibitor and Its Use as a Molecular Probe
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/13417/1/Hong_2013.pdf
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oai:kuscholarworks.ku.edu:1808/252432017-12-19T14:22:39Zcom_1808_100col_1808_101
KU ScholarWorks
author
Ghosh, Suman
author
Shinogle, Heather E.
author
Galeva, Nadezhda A.
author
Dobrowsky, Rick T.
author
Blagg, Brian S. J.
2017-11-02T17:11:52Z
2017-11-02T17:11:52Z
2016-02-12
Ghosh, S., Shinogle, H. E., Galeva, N. A., Dobrowsky, R. T., & Blagg, B. S. (2016). Endoplasmic reticulum-resident heat shock protein 90 (HSP90) isoform glucose-regulated protein 94 (GRP94) regulates cell polarity and cancer cell migration by affecting intracellular transport. Journal of Biological Chemistry, 291(16), 8309-8323.
http://hdl.handle.net/1808/25243
10.1074/jbc.M115.688374
Heat shock protein 90 (HSP90) is a molecular chaperone that is up-regulated in cancer and is required for the folding of numerous signaling proteins. Consequently, HSP90 represents an ideal target for the development of new anti-cancer agents. The human HSP90 isoform, glucose-regulated protein 94 (GRP94), resides in the endoplasmic reticulum and regulates secretory pathways, integrins, and Toll-like receptors, which contribute to regulating immunity and metastasis. However, the cellular function of GRP94 remains underinvestigated. We report that GRP94 knockdown cells are defective in intracellular transport and, consequently, negatively impact the trafficking of F-actin toward the cellular cortex, integrin α2 and integrin αL toward the cell membrane and filopodia, and secretory vesicles containing the HSP90α-AHA1-survivin complex toward the leading edge. As a result, GRP94 knockdown cells form a multipolar spindle instead of bipolar morphology and consequently manifest a defect in cell migration and adhesion.
© The American Society for Biochemistry and Molecular Biology.
Actin
Cell polarity
Heat shock protein 90 (HSP90)
Intracellular trafficking
Survivin aha1
grp94
Integrin
Endoplasmic reticulum chaperone Gp96 controls actomyosin dynamics and protects against pore-forming toxins
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/25243/1/Blagg_2016.pdf
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oai:kuscholarworks.ku.edu:1808/128182018-07-12T17:08:23Zcom_1808_100col_1808_101
KU ScholarWorks
author
Ma, Ze-Qiang
author
Xie, Sheng-Xue
author
Huang, Qing-Qing
author
Nan, Fa-Jun
author
Hurley, Thomas D.
author
Ye, Qi-Zhuang
2014-01-17T21:43:10Z
2014-01-17T21:43:10Z
2007-12-19
Ma, Ze-Qiang, Sheng-Xue Xie, Qing-Qing Huang, Fa-Jun Nan, Thomas D Hurley, and Qi-Zhuang Ye. 2007. “Structural Analysis of Inhibition of E. Coli Methionine Aminopeptidase: Implication of Loop Adaptability in Selective Inhibition of Bacterial Enzymes.” BMC Structural Biology 7:84. http://dx.doi.org/10.1186/1472-6807-7-84.
http://hdl.handle.net/1808/12818
10.1186/1472-6807-7-84
Background: Methionine aminopeptidase is a potential target of future antibacterial and anticancer drugs. Structural analysis of complexes of the enzyme with its inhibitors provides valuable information for structure-based drug design efforts.
Results: Five new X-ray structures of such enzyme-inhibitor complexes were obtained. Analysis of these and other three similar structures reveals the adaptability of a surface-exposed loop bearing Y62, H63, G64 and Y65 (the YHGY loop) that is an integral part of the substrate and inhibitor binding pocket. This adaptability is important for accommodating inhibitors with variations in size. When compared with the human isozymes, this loop either becomes buried in the human type I enzyme due to an N-terminal extension that covers its position or is replaced by a unique insert in the human type II enzyme.
Conclusion: The adaptability of the YHGY loop in E. coli methionine aminopeptidase, and likely in other bacterial methionine aminopeptidases, enables the enzyme active pocket to accommodate inhibitors of differing size. The differences in this adaptable loop between the bacterial and human methionine aminopeptidases is a structural feature that can be exploited to design inhibitors of bacterial methionine aminopeptidases as therapeutic agents with minimal inhibition of the corresponding human enzymes.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Structural analysis of inhibition of E. coli methionine aminopeptidase: implication of loop adaptability in selective inhibition of bacterial enzymes
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/12818/1/Ma_2007.pdf
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oai:kuscholarworks.ku.edu:1808/323142022-01-04T09:01:11Zcom_1808_100col_1808_101
KU ScholarWorks
author
Tang, Zhichao
author
Zhao, Junxing
author
Pearson, Zach J.
author
Boskovic, Zarko V.
author
Wang, Jingxin
2022-01-03T18:47:16Z
2022-01-03T18:47:16Z
2021-04-14
Tang, Z.; Zhao, J.; Pearson, Z.J.; Boskovic, Z.V.; Wang, J. RNA-Targeting Splicing Modifiers: Drug Development and Screening Assays. Molecules 2021, 26, 2263. https://doi.org/10.3390/molecules26082263
http://hdl.handle.net/1808/32314
10.3390/molecules26082263
https://orcid.org/ 0000-0002-6305-6218https://orcid.org/ 0000-0001-9376-527Xhttps://orcid.org/ 0000-0002-9414-4093
PMC8070285
RNA splicing is an essential step in producing mature messenger RNA (mRNA) and other RNA species. Harnessing RNA splicing modifiers as a new pharmacological modality is promising for the treatment of diseases caused by aberrant splicing. This drug modality can be used for infectious diseases by disrupting the splicing of essential pathogenic genes. Several antisense oligonucleotide splicing modifiers were approved by the U.S. Food and Drug Administration (FDA) for the treatment of spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). Recently, a small-molecule splicing modifier, risdiplam, was also approved for the treatment of SMA, highlighting small molecules as important warheads in the arsenal for regulating RNA splicing. The cellular targets of these approved drugs are all mRNA precursors (pre-mRNAs) in human cells. The development of novel RNA-targeting splicing modifiers can not only expand the scope of drug targets to include many previously considered “undruggable” genes but also enrich the chemical-genetic toolbox for basic biomedical research. In this review, we summarized known splicing modifiers, screening methods for novel splicing modifiers, and the chemical space occupied by the small-molecule splicing modifiers.
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.
Alternative splicing
High-throughput screening
Antisense oligonucleotide
Small molecule
Splicing modifier
RNA-targeting
RNA-Targeting Splicing Modifiers: Drug Development and Screening Assays
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/32314/1/Tang_2021.pdf
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oai:kuscholarworks.ku.edu:1808/240282018-07-17T15:43:52Zcom_1808_100col_1808_101
KU ScholarWorks
author
Tong, Xiaoqin
author
Zhang, Huaping
author
Timmermann, Barbara N.
2017-05-08T20:32:16Z
2017-05-08T20:32:16Z
2011-12
Tong, Xiaoqin, Huaping Zhang, and Barbara N. Timmermann. “Chlorinated Withanolides from Withania Somnifera.” Phytochemistry letters 4.4 (2011): 411–414.
http://hdl.handle.net/1808/24028
10.1016/j.phytol.2011.04.016
PMC3223914
A chlorinated withanolide, 6α-chloro-5β,17α-dihydroxywithaferin A (1), and nine known withanolides, 6α-chloro-5β-hydroxywithaferin A (2), (22R)-5β-formyl-6β,27-dihydroxy-1-oxo-4-norwith-24-enolide, withaferin A, 2,3-dihydrowithaferin A, 3-methoxy-2,3-dihydrowithaferin A, 2,3-didehydrosomnifericin, withanone, withanoside IV and withanoside X, were isolated from Withania somnifera (Solanaceae). All structures were elucidated on the basis of spectroscopic methods (IR, HRESIMS, 1D/2D NMR). X-ray crystallography confirmed the absolute configuration of 1.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Chlorinated withanolide
Withania somnifera
Solanaceae
NMR
Crystal structure
Chlorinated Withanolides from Withania somnifera
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/24028/1/timmermann_chlorinated.pdf
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oai:kuscholarworks.ku.edu:1808/247012019-04-12T14:23:43Zcom_1808_100col_1808_101
KU ScholarWorks
author
Perchellet, Jean-Pierre H.
author
Perchellet, Elisabeth M.
author
Crow, Kyle R.
author
Buszek, Keith R.
author
Brown, Neil
author
Ellappan, Sampathkumar
author
Gao, Ge
author
Luo, Diheng
author
Minatoya, Machiko
author
Lushington, Gerald H.
2017-06-28T22:08:08Z
2017-06-28T22:08:08Z
2009-11
PERCHELLET, J.-P. H., PERCHELLET, E. M., CROW, K. R., BUSZEK, K. R., BROWN, N., ELLAPPAN, S., … LUSHINGTON, G. H. (2009). Novel synthetic inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity that inhibit tumor cell proliferation and are structurally unrelated to existing statins. International Journal of Molecular Medicine, 24(5), 633–643.
http://hdl.handle.net/1808/24701
10.3892/ijmm_00000274
Pilot-scale libraries of eight-membered medium ring lactams (MRLs) and related tricyclic compounds (either seven-membered lactams, thiolactams or amines) were screened for their ability to inhibit the catalytic activity of human recombinant 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase in vitro. A dozen of the synthetic compounds mimic the inhibition of purified HMG-CoA reductase activity caused by pravastatin, fluvastatin and sodium salts of lovastatin, mevastatin and simvastatin in this cell-free assay, suggesting direct interaction with the rate-limiting enzyme of cholesterol biosynthesis. Moreover, several MRLs inhibit the metabolic activity of L1210 tumor cells in vitro to a greater degree than fluvastatin, lovastatin, mevastatin and simvastatin, whereas pravastatin is inactive. Although the correlation between the concentration-dependent inhibitions of HMG-CoA reductase activity over 10 min in the cell-free assay and L1210 tumor cell proliferation over 4 days in culture is unclear, some bioactive MRLs elicit interesting combinations of statin-like (IC50: 7.4-8.0 µM) and anti-tumor (IC50: 1.4-2.3 µM) activities. The HMG-CoA reductase-inhibiting activities of pravastatin and an MRL persist in the presence of increasing concentrations of NADPH. But increasing concentrations of HMG-CoA block the HMG-CoA reductase-inhibiting activity of pravastatin without altering that of an MRL, suggesting that MRLs and existing statins may have different mechanisms of enzyme interaction and inhibition. When tested together, suboptimal concentrations of synthetic MRLs and existing statins have additive inhibitory effects on HMG-CoA reductase activity. Preliminary molecular docking studies with MRL-based inhibitors indicate that these ligands fit sterically well into the HMG-CoA reductase statin-binding receptor model and, in contrast to mevastatin, may occupy a narrow channel housing the pyridinium moiety on NADP+.
Novel synthetic inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity that inhibit tumor cell proliferation and are structurally unrelated to existing statins
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/24701/1/Lushington_2009.pdf
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oai:kuscholarworks.ku.edu:1808/235832019-04-12T14:12:41Zcom_1808_100col_1808_101
KU ScholarWorks
author
Salunke, Deepak B.
author
Connelly, Seth W.
author
Shukla, Nikunj M.
author
Hermanson, Alec R.
author
Fox, Lauren M.
author
David, Sunil A.
2017-04-06T16:18:22Z
2017-04-06T16:18:22Z
2013-07-25
Salunke, D. B., Connelly, S. W., Shukla, N. M., Hermanson, A. R., Fox, L. M., & David, S. A. (2013). Design and Development of Stable, Water-soluble, Human Toll-like Receptor 2-Specific, Monoacyl Lipopeptides as Candidate Vaccine Adjuvants. Journal of Medicinal Chemistry, 56(14), 10.1021/jm400620g. http://doi.org/10.1021/jm400620g
http://hdl.handle.net/1808/23583
10.1021/jm400620g
https://orcid.org/0000-0002-1241-9146
Antigens in modern subunit vaccines are largely soluble and poorly immunogenic proteins inducing relatively short-lived immune responses. Appropriate adjuvants initiate early innate immune responses, amplifying subsequent adaptive immune responses. Agonists of TLR2 are devoid of significant pro-inflammatory activity in ex vivo human blood models, and yet potently adjuvantic, suggesting that this chemotype may be a safe and effective adjuvant. Our earlier work on the monoacyl lipopeptide class of TLR2 agonists led to the design of a highly potent lead, but with negligible aqueous solubility, necessitating the reintroduction of aqueous solubility. We explored several strategies of introducing ionizable groups on the lipopeptide, as well as the systematic evaluation of chemically stable bioisosteres of the ester-linked palmitoyl group. These studies have led to a fully optimized, chemically stable, and highly water-soluble, human TLR2-specific agonist, which was found to have an excellent safety profile and displayed prominent adjuvantic activities in rabbit models.
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm900254k.
TLR2
TLR2 agonists
Vaccine adjuvants
Innate immunity
Design and Development of Stable, Water-soluble, Human Toll-like Receptor 2-Specific, Monoacyl Lipopeptides as Candidate Vaccine Adjuvants
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23583/1/Salunke_2013.pdf
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oai:kuscholarworks.ku.edu:1808/245562019-04-12T14:21:13Zcom_1808_100col_1808_101
KU ScholarWorks
author
Lönnfors, Max
author
Engberg, Oskar
author
Peterson, Blake R.
author
Slotte, J. Peter
2017-06-20T17:12:22Z
2017-06-20T17:12:22Z
2012-01-10
Lönnfors, M., Engberg, O., Peterson, B. R., & Slotte, J. P. (2012). Interaction of 3β-amino-5-cholestene with phospholipids in binary and ternary bilayer membranes. Langmuir, 28(1), 648–655. http://doi.org/10.1021/la203589u
http://hdl.handle.net/1808/24556
10.1021/la203589u
PMC3265605
3β-Amino-5-cholestene (aminocholesterol) is a synthetic sterol whose properties in bilayer membranes have been examined. In fluid palmitoyl sphingomyelin (PSM) bilayers, aminocholesterol and cholesterol were equally effective in increasing acyl chain order, based on changes in diphenylhexatriene (DPH) anisotropy. In fluid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) bilayers, aminocholesterol ordered acyl chains, but slightly less efficiently than cholesterol. Aminocholesterol eliminated the PSM and DPPC gel-to-liquid crystalline phase transition enthalpy linearly with concentration, and the enthalpy approached zero at 30 mol% sterol. Whereas cholesterol was able to increase the thermostability of ordered PSM domains in a fluid bilayer, aminocholesterol under equal conditions failed to do this, suggesting that its interaction with PSM was not as favorable as cholesterol’s. In ternary mixed bilayers, containing 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), PSM or DPPC, and cholesterol at proportions to contain a liquid-ordered phase (60:40 by mol of POPC and PSM or DPPC, and 30 mol% cholesterol), the average life-time of trans parinaric acid (tPA) was close to 20 ns. When cholesterol was replaced with aminocholesterol in such mixed bilayers, the average life-time of tPA was only marginally shorter (about 18 ns). This observation, together with acyl chain ordering data, clearly shows that aminocholesterol was able to form a liquid-ordered phase with saturated PSM or DPPC. We conclude that aminocholesterol should be a good sterol replacement in model membrane systems for which a partial positive charge is deemed beneficial.
Membrane structure
Differential scanning calorimetry
Cholestatrienol
Trans parinaric acid
Interaction of 3â-amino-5-cholestene with phospholipids in binary and ternary bilayer membranes
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/24556/1/Peterson_2012.pdf
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oai:kuscholarworks.ku.edu:1808/309382020-12-02T09:00:56Zcom_1808_100col_1808_101
KU ScholarWorks
author
Motiwala, Hashim F.
author
Yin, Qin
author
Aubé, Jeffrey
2020-12-01T16:07:12Z
2020-12-01T16:07:12Z
2015-12-29
Motiwala, H. F., Yin, Q., & Aubé, J. (2015). Improved Schmidt Conversion of Aldehydes to Nitriles Using Azidotrimethylsilane in 1,1,1,3,3,3-Hexafluoro-2-propanol. Molecules (Basel, Switzerland), 21(1), E45. https://doi.org/10.3390/molecules21010045
http://hdl.handle.net/1808/30938
10.3390/molecules21010045
https://orcid.org/0000-0003-1049-5767
PMC6273554
The Schmidt reaction of aromatic aldehydes using a substoichiometric amount (40 mol %) of triflic acid is described. Low catalyst loading was enabled by a strong hydrogen-bond-donating solvent hexafluoro-2-propanol (HFIP). This improved protocol tolerates a broad scope of aldehydes with diverse functional groups and the corresponding nitriles were obtained in good to high yields without the need for aqueous work up.
© 2015 by the authors. Licensee MDPI, Basel, Switzerland.
Schmidt reaction
Aldehydes
Nitriles
HFIP
Improved Schmidt Conversion of Aldehydes to Nitriles Using Azidotrimethylsilane in 1,1,1,3,3,3-Hexafluoro-2-propanol
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/30938/1/Motiwala_2015.pdf
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oai:kuscholarworks.ku.edu:1808/240082019-04-12T14:16:24Zcom_1808_100col_1808_101
KU ScholarWorks
author
Sally, Elliott J.
author
Xu, Heng
author
Dersch, Christina M.
author
Hsin, Ling-Wei
author
Chang, Li-Te
author
Prisinzano, Thomas E.
author
Simpson, Denise S.
author
Giuvelis, Denise
author
Rice, Kenner C.
author
Jacobson, Arthur E.
author
Cheng, Kejun
author
Bilsky, Edward J.
author
Rothman, Richard B.
2017-05-08T16:56:32Z
2017-05-08T16:56:32Z
2010-04
Sally, E. J., Xu, H., Dersch, C. M., Hsin, L.-W., Chang, L.-T., Prisinzano, T. E., Simpson, D. S., Giuvelis, D., Rice, K. C., Jacobson, A. E., Cheng, K., Bilsky, E. J. and Rothman, R. B. (2010), Identification of a novel “almost neutral” μ-opioid receptor antagonist in CHO cells expressing the cloned human μ-opioid receptor. Synapse, 64: 280–288. doi:10.1002/syn.20723
http://hdl.handle.net/1808/24008
10.1002/syn.20723
PMC2821452
The basal (constitutive) activity of G protein-coupled receptors allows for the measurement of inverse agonist activity. Some competitive antagonists turn into inverse agonists under conditions where receptors are constitutively active. In contrast, neutral antagonists have no inverse agonist activity, and they block both agonist and inverse agonist activity. The mu opioid receptor (MOR) demonstrates detectable constitutive activity only after a state of dependence is produced by chronic treatment with a MOR agonist. We therefore sought to identify novel MOR inverse agonists, and novel neutral MOR antagonists in both untreated and agonist-treated MOR cells. CHO cells expressing the cloned human mu receptor (hMOR-CHO cells) were incubated for 20 hr with medium (control) or 10 μM (2S,4aR,6aR,7R,9S,10aS,10bR)-9-(benzoyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho-[2,1-c]pyran-7-carboxylic acid methyl ester (herkinorin, HERK). HERK-treatment generates a high degree of basal signaling and enhances the ability to detect inverse agonists. [35S]-GTP-γ-S assays were conducted using established methods. We screened 21 MOR “antagonists” using membranes prepared from HERK-treated hMOR-CHO cells. All antagonists, including CTAP and 6β-naltrexol, were inverse agonists. However, LTC-2 7 4 ( (-)-3-cyclopropylmethyl-2,3,4,4aα,5,6,7,7aα-octahydro-1H-benzofuro[3,2-e]isoquinolin-9-ol)) showed the lowest efficacy as an inverse agonist, and, at concentrations less than 5 nM, had minimal effects on basal [35S]-GTP-γ-S binding. Other efforts in this study identified KC-2-009 ((+)-3-((1R,5S)-2-((Z)-3-Phenylallyl)-2-azabicyclo[3.3.1]nonan-5-yl)phenol hydrochloride) as an inverse agonist at untreated MOR cells. In HERK-treated cells, KC-2-009 had the highest efficacy as an inverse agonist. In summary, we identified a novel and selective MOR inverse agonist (KC-2-009), and a novel MOR antagonist (LTC-274) that shows the least inverse agonist activity among 21 MOR antagonists. LTC-274 is a promising lead compound for developing a true MOR neutral antagonist.
Identification of a Novel “Almost Neutral” Mu Opioid Receptor Antagonist in CHO Cells Expressing the Cloned Human Mu Opioid Receptor
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/24008/1/Prisinzano_2010.pdf
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oai:kuscholarworks.ku.edu:1808/132372018-07-12T17:32:09Zcom_1808_100col_1808_101
KU ScholarWorks
author
Fink, Brian D.
author
O'Malley, Yunxia
author
Dake, Brian L.
author
Ross, Nicolette C.
author
Prisinzano, Thomas E.
author
Sivitz, William I.
2014-03-18T19:43:23Z
2014-03-18T19:43:23Z
2009-01-22
Fink, B. D., O’Malley, Y., Dake, B. L., Ross, N. C., Prisinzano, T. E., & Sivitz, W. I. (2009). Mitochondrial Targeted Coenzyme Q, Superoxide, and Fuel Selectivity in Endothelial Cells. PLoS ONE, 4(1). http://dx.doi.org/10.1371/journal.pone.0004250
http://hdl.handle.net/1808/13237
10.1371/journal.pone.0004250
Background
Previously, we reported that the “antioxidant” compound “mitoQ” (mitochondrial-targeted ubiquinol/ubiquinone) actually increased superoxide production by bovine aortic endothelial (BAE) cell mitochondria incubated with complex I but not complex II substrates.
Methods and Results
To further define the site of action of the targeted coenzyme Q compound, we extended these studies to include different substrate and inhibitor conditions. In addition, we assessed the effects of mitoquinone on mitochondrial respiration, measured respiration and mitochondrial membrane potential in intact cells, and tested the intriguing hypothesis that mitoquinone might impart fuel selectivity in intact BAE cells. In mitochondria respiring on differing concentrations of complex I substrates, mitoquinone and rotenone had interactive effects on ROS consistent with redox cycling at multiple sites within complex I. Mitoquinone increased respiration in isolated mitochondria respiring on complex I but not complex II substrates. Mitoquinone also increased oxygen consumption by intact BAE cells. Moreover, when added to intact cells at 50 to 1000 nM, mitoquinone increased glucose oxidation and reduced fat oxidation, at doses that did not alter membrane potential or induce cell toxicity. Although high dose mitoquinone reduced mitochondrial membrane potential, the positively charged mitochondrial-targeted cation, decyltriphenylphosphonium (mitoquinone without the coenzyme Q moiety), decreased membrane potential more than mitoquinone, but did not alter fuel selectivity. Therefore, non-specific effects of the positive charge were not responsible and the quinone moiety is required for altered nutrient selectivity.
Conclusions
In summary, the interactive effects of mitoquinone and rotenone are consistent with redox cycling at more than one site within complex I. In addition, mitoquinone has substrate dependent effects on mitochondrial respiration, increases repiration by intact cells, and alters fuel selectivity favoring glucose over fatty acid oxidation at the intact cell level.
This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
Fuels
Glucose
Glucose metabolism
Membrane potential
Mitochondria
Oleates
Oxidation
Oxidation-reduction reactions
Mitochondrial Targeted Coenzyme Q, Superoxide, and Fuel Selectivity in Endothelial Cells
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/13237/1/Fink.pdf
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oai:kuscholarworks.ku.edu:1808/200342018-12-19T18:48:42Zcom_1808_100col_1808_101
KU ScholarWorks
author
Lu, Rongtao
author
Liu, Jianwei
author
Luo, Hongfu
author
Chikan, Viktor
author
Wu, Judy Z.
2016-02-12T21:35:06Z
2016-02-12T21:35:06Z
2016-01-18
Lu, Rongtao, Jianwei Liu, Hongfu Luo, Viktor Chikan, and Judy Z. Wu. "Graphene/GaSe-Nanosheet Hybrid: Towards High Gain and Fast Photoresponse." Sci. Rep. Scientific Reports 6 (2016): 19161. doi:10.1038/srep19161
http://hdl.handle.net/1808/20034
10.1038/srep19161
While high photoconductive gain has been recently achieved in graphene-based hybrid phototransistors using semiconductor two-dimensional transition/post-transition metal dichalcogenides or quantum dots sensitizers, obtaining fast photoresponse simutaneously remains a challenge that must be addressed for practical applications. In this paper we report a graphene/GaSe nanosheets hybrid photodetector, in which GaSe nanosheets provide a favorable geometric link to graphene conductive layer through van Der Waals force. After a vacuum annealing process, a high gain in exceeding 107 has been obtained simitaneously with a dynamic response time of around 10 ms for both light on and off. We attribute the high performance to the elimination of possible deep charge traps, most probably at the graphene/GaSe nanosheets interface. This result demonstrates high photoconductive gain and fast photoresponse can be achieved simultaneously and a clean interface is the key to the high performance of these hybrid devices.
This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Graphene/GaSe-Nanosheet Hybrid: Towards High Gain and Fast Photoresponse
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/20034/1/wu_graphene.pdf
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oai:kuscholarworks.ku.edu:1808/233222019-04-12T14:24:07Zcom_1808_100col_1808_101
KU ScholarWorks
author
Qiao, Yupu
author
Zhu, Lingui
author
Ambler, Brett R.
author
Altman, Ryan A.
2017-03-01T21:06:02Z
2017-03-01T21:06:02Z
2015-01-01
Qiao, Yupu, Lingui Zhu, Brett Ambler, and Ryan Altman. "Decarboxylative Fluorination Strategies for Accessing Medicinally- Relevant Products." Current Topics in Medicinal Chemistry 14.7 (2014): 966-78.
http://hdl.handle.net/1808/23322
10.2174/1568026614666140202210850
Fluorinated organic compounds have a long history in medicinal chemistry, and synthetic methods to access target fluorinated compounds are undergoing a revolution. One powerful strategy for the installation of fluorine-containing functional groups includes decarboxylative reactions. Benefits of decarboxylative approaches potentially include: 1) readily available substrates or reagents 2) mild reaction conditions; 3) simplified purification. This focus review highlights the applications of decarboxylation strategies for fluorination reactions to access compounds with biomedical potential. The manuscript highlights on two general strategies, fluorination by decarboxylative reagents and by decarboxylation of substrates. Where relevant, examples of medicinally useful compounds that can be accessed using these strategies are highlighted.
Decarboxylation
Fluorination
Difluoromethylation
Trifluoromethylation
Copper
Decarboxylative Fluorination Strategies for Accessing Medicinally-relevant Products
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23322/1/altman_decarboxylative.pdf
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oai:kuscholarworks.ku.edu:1808/220952018-07-16T16:57:49Zcom_1808_100col_1808_101
KU ScholarWorks
author
Dunn, Diana M.
author
Woodford, Mark R.
author
Truman, Andrew W.
author
Jensen, Sandra M.
author
Schulman, Jacqualyn
author
Caza, Tiffany
author
Remillard, Taylor C.
author
Loiselle, David
author
Wolfgeher, Donald
author
Blagg, Brian S. J.
2016-11-30T17:57:12Z
2016-11-30T17:57:12Z
2015-08-11
Dunn, D. M., Woodford, M. R., Truman, A. W., Jensen, S. M., Schulman, J., Caza, T., … Mollapour, M. (2015). c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells. Cell Reports, 12(6), 1006–1018. doi:10.1016/j.celrep.2015.07.004
http://hdl.handle.net/1808/22095
10.1016/j.celrep.2015.07.004
The ability of Heat Shock Protein 90 (Hsp90) to hydrolyze ATP is essential for its chaperone function. The co-chaperone Aha1 stimulates Hsp90 ATPase activity, tailoring the chaperone function to specific “client” proteins. The intracellular signaling mechanisms directly regulating Aha1 association with Hsp90 remain unknown. Here, we show that c-Abl kinase phosphorylates Y223 in human Aha1 (hAha1), promoting its interaction with Hsp90. This, consequently, results in an increased Hsp90 ATPase activity, enhances Hsp90 interaction with kinase clients, and compromises the chaperoning of non-kinase clients such as glucocorticoid receptor and CFTR. Suggesting a regulatory paradigm, we also find that Y223 phosphorylation leads to ubiquitination and degradation of hAha1 in the proteasome. Finally, pharmacologic inhibition of c-Abl prevents hAha1 interaction with Hsp90, thereby hypersensitizing cancer cells to Hsp90 inhibitors both in vitro and ex vivo.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/22095/1/Blagg_2015.pdf
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oai:kuscholarworks.ku.edu:1808/245742019-04-12T14:22:05Zcom_1808_100col_1808_101
KU ScholarWorks
author
Prevatt-Smith, Katherine M.
author
Lovell, Kimberly M.
author
Simpson, Denise S.
author
Day, Victor W.
author
Douglas, Justin T.
author
Bosch, Peter
author
Dersch, Christina M.
author
Rothman, Richard B.
author
Kivell, Bronwyn
author
Prisinzano, Thomas E.
2017-06-22T17:02:21Z
2017-06-22T17:02:21Z
2011-12
Prevatt-Smith, K. M., Lovell, K. M., Simpson, D. S., Day, V. W., Douglas, J. T., Bosch, P., … Prisinzano, T. E. (2011). Potential Drug Abuse Therapeutics Derived from the Hallucinogenic Natural Product Salvinorin A. MedChemComm, 2(12), 1217–1222. http://doi.org/10.1039/C1MD00192B
http://hdl.handle.net/1808/24574
10.1039/C1MD00192B.
PMC3307802
Previous structure-activity relationship studies of salvinorin A have shown that modification of the acetate functionality off the C-2 position to a methoxy methyl or methoxy ethyl ether moiety leads to increased potency at KOP receptors. However, the reason for this increase remains unclear. Here we report our efforts towards the synthesis and evaluation of C-2 constrained analogs of salvinorin A. These analogs were evaluated at opioid receptors in radioligand binding experiments as well as in the GTP-γ-S functional assay. One compound, 5, was found to have affinity and potency at κ opioid (KOP) receptors comparable to salvinorin A. In further studies, 5 was found to attenuate cocaine-induced drug seeking behavior in rats comparably to salvinorin A. This finding represents the first example of a salvinorin A analog that has demonstrated anti-addictive capabilities.
Potential Drug Abuse Therapeutics Derived from the Hallucinogenic Natural Product Salvinorin A
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/24574/1/Prisinzano_2011.pdf
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URL
https://kuscholarworks.ku.edu/bitstream/1808/24574/3/Prisinzano_2011.pdf.txt
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28959
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oai:kuscholarworks.ku.edu:1808/226092018-07-16T17:28:30Zcom_1808_100col_1808_101
KU ScholarWorks
author
Hymel, David
author
Peterson, Blake R.
2017-01-12T18:19:40Z
2017-01-12T18:19:40Z
2013-06-15
Hymel, David, and Blake R. Peterson. "Synthetic Cell Surface Receptors for Delivery of Therapeutics and Probes." Advanced Drug Delivery Reviews 64.9 (2012): 797-810.
http://hdl.handle.net/1808/22609
10.1016/j.addr.2012.02.007
Receptor-mediated endocytosis is a highly efficient mechanism for cellular uptake of membrane-impermeant ligands. Cells use this process to acquire nutrients, initiate signal transduction, promote development, regulate neurotransmission, and maintain homeostasis. Natural receptors that participate in receptor-mediated endocytosis are structurally diverse, ranging from large transmembrane proteins to small glycolipids embedded in the outer leaflet of cellular plasma membranes. Despite their vast structural differences, these receptors share common features of binding to extracellular ligands, clustering in dynamic membrane regions that pinch off to yield intracellular vesicles, and accumulation of receptor-ligand complexes in membrane-sealed endosomes. Receptors typically dissociate from ligands in endosomes and cycle back to the cell surface, whereas internalized ligands are usually delivered into lysosomes, where they are degraded, but some can escape and penetrate into the cytosol. Here, we review efforts to develop synthetic cell surface receptors, defined as nonnatural compounds, exemplified by mimics of cholesterol, that insert into plasma membranes, bind extracellular ligands including therapeutics, probes, and endogenous proteins, and engage endocytic membrane trafficking pathways. By mimicking natural mechanisms of receptor-mediated endocytosis, synthetic cell surface receptors have the potential to function as prosthetic molecules capable of seamlessly augmenting the endocytic uptake machinery of living mammalian cells.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Receptors
Ligands
Cholesterol
Lipids
Endocytosis
Trafficking
Recycling
Delivery
Endosomes
Membranes
Fluorescence
Vancomycin
Synthetic Cell Surface Receptors for Delivery of Therapeutics and Probes
Article
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https://kuscholarworks.ku.edu/bitstream/1808/22609/1/peterson_synthetic.pdf
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oai:kuscholarworks.ku.edu:1808/343712023-06-14T06:06:33Zcom_1808_100col_1808_101
KU ScholarWorks
author
Shinde, Anand H.
author
Dhokale, Ranjeet A.
author
Mague, Joel T.
author
Sathyamoorthi, Shyam
2023-06-13T20:03:10Z
2023-06-13T20:03:10Z
2022-07-28
Shinde, A. H., Dhokale, R. A., Mague, J. T., & Sathyamoorthi, S. (2022). Highly Stereospecific Cyclizations of Homoallylic Silanols. The Journal of organic chemistry, 87(16), 11237–11252. https://doi.org/10.1021/acs.joc.2c01170
https://hdl.handle.net/1808/34371
10.1021/acs.joc.2c01170
https://orcid.org/0000-0003-1966-8505https://orcid.org/0000-0003-4705-7349
PMC10019461
We demonstrate that di-tert-butylsilanols are competent nucleophiles for the intramolecular interception of palladium π-allyl species. In these reactions, allyl ethyl carbonates are the best precursors for the formation of palladium π-allyl intermediates, and [(Cinnamyl)PdCl]2/BINAP is superior to other Pd salt/ligand framework combinations. Our optimized protocol is compatible with a variety of silanol substrates. Importantly, the cyclization is perfectly stereospecific, proceeding via an anti-syn mechanism, which stands in contrast to reported analogous reactions of alcohols and phenols, known to proceed via an anti-anti mechanism. The alkenes in the product dioxasilinanes serve as blank slates for further functionalization.
Copyright © 2022 American Chemical Society
Highly Stereospecific Cyclizations of Homoallylic Silanols
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/34371/1/Shinde_2022.pdf
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oai:kuscholarworks.ku.edu:1808/176492019-04-12T14:52:47Zcom_1808_100col_1808_101
KU ScholarWorks
author
Warshakoon, Hemamali J.
author
Burns, Mark R.
author
David, Sunil A.
2015-05-07T20:25:00Z
2015-05-07T20:25:00Z
2009-01
Warshakoon et al. "Structure-Activity Relationships of Antimicrobial and Lipoteichoic Acid-Sequestering Properties in Polyamine Sulfonamides." Antimicrob. Agents Chemother. January 2009 vol. 53 no. 1 57-62.
http://dx.doi.org/10.1128/AAC.00812-08
http://hdl.handle.net/1808/17649
10.1128/AAC.00812-08
We have recently confirmed that lipoteichoic acid (LTA), a major constituent of the gram-positive bacterial surface, is the endotoxin of gram-positive bacteria that induces proinflammatory molecules in a Toll-like receptor 2 (TLR2)-dependent manner. LTA is an anionic amphipath whose physicochemical properties are similar to those of lipopolysaccharide (LPS), which is found on the outer leaflet of the outer membranes of gram-negative organisms. Hypothesizing that compounds that sequester LPS could also bind to and inhibit LTA-induced cellular activation, we screened congeneric series of polyamine sulfonamides which we had previously shown effectively neutralized LPS both in vitro and in animal models of endotoxemia. We observed that these compounds do bind to and neutralize LTA, as reflected by the inhibition of TLR2-mediated NF-κB induction in reporter gene assays. Structure-activity studies showed a clear dependence of the acyl chain length on activity against LTA in compounds with spermine and homospermine scaffolds. We then sought to examine possible correlations between the neutralizing potency toward LTA and antimicrobial activity in Staphylococcus aureus. A linear relationship between LTA sequestration activity and antimicrobial activity for compounds with a spermine backbone was observed, while all compounds with a homospermine backbone were equally active against S. aureus, regardless of their neutralizing potency toward LTA. These results suggest that the number of protonatable charges is a key determinant of the activity toward the membranes of gram-positive bacteria. The development of resistance to membrane-active antibiotics has been relatively slower than that to conventional antibiotics, and it is possible that compounds such as the acylpolyamines may be useful clinically, provided that they have an acceptable safety profile and margin of safety. A more detailed understanding of the mechanisms of interactions of these compounds with LPS and LTA, as well as the gram-negative and -positive bacterial cell surfaces, will be instructive and should allow the rational design of analogues which combine antisepsis and antibacterial properties.
Structure-Activity Relationships of Antimicrobial and Lipoteichoic Acid-Sequestering Properties in Polyamine Sulfonamides
Article
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URL
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oai:kuscholarworks.ku.edu:1808/235942019-04-12T14:12:41Zcom_1808_100col_1808_101
KU ScholarWorks
author
Li, Kelin
author
Frankowski, Kevin J.
author
Belon, Craig A.
author
Neuenswander, Benjamin
author
Ndjomou, Jean
author
Hanson, Alicia M.
author
Shanahan, Matthew A.
author
Schoenen, Frank J.
author
Blagg, Brian S. J.
author
Aubé, Jeffrey
author
Frick, David N.
2017-04-06T17:20:13Z
2017-04-06T17:20:13Z
2012-04-12
Li, K., Frankowski, K. J., Belon, C. A., Neuenswander, B., Ndjomou, J., Hanson, A. M., … Frick, D. N. (2012). Optimization of Potent Hepatitis C Virus NS3 Helicase Inhibitors Isolated from the Yellow Dyes Thioflavine S and Primuline. Journal of Medicinal Chemistry, 55(7), 3319–3330. http://doi.org/10.1021/jm300021v
http://hdl.handle.net/1808/23594
10.1021/jm300021v
A screen for hepatitis C virus (HCV) NS3 helicase inhibitors revealed that the commercial dye thioflavine S was the most potent inhibitor of NS3-catalyzed DNA and RNA unwinding in the 827-compound National Cancer Institute Mechanistic Set. Thioflavine S and the related dye primuline were separated here into their pure components, all of which were oligomers of substituted benzothiazoles. The most potent compound (P4), a benzothiazole tetramer, inhibited unwinding >50% at 2±1 μM, inhibited the subgenomic HCV replicon at 10 μM, and was not toxic at 100 μM. Because P4 also interacted with DNA, more specific analogs were synthesized from the abundant dimeric component of primuline. Some of the 29 analogs prepared retained ability to inhibit HCV helicase but did not appear to interact with DNA. The most potent of these specific helicase inhibitors (compound 17) was active against the replicon and inhibited the helicase more than 50% at 2.6±1 μM.
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm300021v.
Hepatitis C virus
NS3
Helicase
Protease
ATPase
Benzothiazoles
Optimization of Potent Hepatitis C Virus NS3 Helicase Inhibitors Isolated from the Yellow Dyes Thioflavine S Primuline
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23594/1/Frankowski_2012.pdf
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oai:kuscholarworks.ku.edu:1808/59362019-04-12T14:33:40Zcom_1808_8219com_1808_100col_1808_8220col_1808_101
KU ScholarWorks
author
Hanzlik, Robert P.
author
Fowler, Stephen C.
author
Fisher, D. H.
2010-03-17T19:01:29Z
2010-03-17T19:01:29Z
2005-06
Hanzlik RP, Fowler SC, Fisher DH. Relative bioavailability of calcium from calcium formate, calcium citrate, and calcium carbonate. J Pharmacol Exp Ther. 2005 Jun; 313(3):1217-22.
http://hdl.handle.net/1808/5936
Published Abstract: Calcium is an essential nutrient required in substantial amounts, but many diets are deficient in calcium making supplementation necessary or desirable. The objective of this study was to compare the oral bioavailability of calcium from calcium formate, a new experimental dietary calcium supplement, to that of calcium citrate and calcium carbonate. In a four-way crossover study, either a placebo or 1200 mg of calcium as calcium carbonate, calcium citrate, or calcium formate were administered orally to 14 healthy adult female volunteers who had fasted overnight. After calcium carbonate, the maximum rise in serum calcium (~4%) and the fall in serum intact para-thyroid hormone 1–84 (iPTH) (~20–40%) did not differ significantly from placebo. After calcium citrate, the changes were modestly but significantly (p < 0.05) greater, but only at 135 to 270 min after ingestion. In contrast, within 60 min after calcium formate serum calcium rose by approximately 15% and serum iPTH fell by 70%. The mean increment in area under the plasma concentration-time curve (0–270 min) for serum calcium after calcium formate (378 mg∙min/dl) was double that for calcium citrate (178 mg∙min/dl; p < 0.01), whereas the latter was only modestly greater than either placebo (107; p < 0.05) or calcium carbonate (91; p < 0.05). In this study, calcium formate was clearly superior to both calcium carbonate and calcium citrate in ability to deliver calcium to the bloodstream after oral administration. Calcium formate may offer significant advantages as a dietary calcium supplement.
Relative bioavailability of calcium from calcium formate, calcium citrate, and calcium carbonate
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/5936/3/Relative%20Bioavailability_Hanzlik_2.pdf
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Relative Bioavailability_Hanzlik_2.pdf.txt
oai:kuscholarworks.ku.edu:1808/236262019-04-12T14:13:27Zcom_1808_100col_1808_101
KU ScholarWorks
author
Agnihotri, Geetanjali
author
Crall, Breanna M.
author
Lewis, Tyler C.
author
Day, Timothy P.
author
Balakrishna, Rajalakshmi
author
Warshakoon, Hemamali J.
author
Malladi, Subbalakshmi S.
author
David, Sunil A.
2017-04-12T14:37:01Z
2017-04-12T14:37:01Z
2011-12-08
Agnihotri, G., Crall, B. M., Lewis, T. C., Day, T. P., Balakrishna, R., Warshakoon, H. J., … David, S. A. (2011). Structure-Activity Relationships in Toll-like Receptor 2-Agonists Leading to Simplified Monoacyl Lipopeptides. Journal of Medicinal Chemistry, 54(23), 8148–8160. http://doi.org/10.1021/jm201071e
http://hdl.handle.net/1808/23626
10.1021/jm201071e
https://orcid.org/0000-0003-2197-1917
Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM2CS) compounds are potential vaccine adjuvants. In continuation of previously reported structure-activity relationships on this chemotype, we have determined that at least one acyl group of optimal length (C16) and an appropriately orientated ester carbonyl group is essential for TLR2-agonistic activity. The spacing between one of the palmitoyl ester carbonyl and the thioether is crucial to allow for an important H-bond, which observed in the crystal structure of the lipopeptide:TLR2 complex; consequently, activity is lost in homologated compounds. Penicillamine-derived analogues are also inactive, likely due to unfavorable steric interactions with the carbonyl of Ser 12 in TLR2. The thioether in this chemotype can be replaced with a selenoether. Importantly, the thioglycerol motif can be dispensed with altogether, and can be replaced with a thioethanol bridge. These results have led to a structurally simpler, synthetically more accessible, and water-soluble analogue possessing strong TLR2-agonistic activities in human blood.
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm201071e.
TLR2
TLR2 agonists
Vaccine adjuvants
Innate immunity
Lipopeptides
Structure-Activity Relationships in Toll-like Receptor 2-Agonists Leading to Simplified Monoacyl Lipopeptides
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23626/1/Crall_2011.pdf
File
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oai:kuscholarworks.ku.edu:1808/175642019-04-12T14:14:22Zcom_1808_100col_1808_101
KU ScholarWorks
author
Khera, Smriti
author
Carducci, Michael D.
author
Gu, Jian-Qiao
author
Timmermann, Barbara N.
2015-05-04T17:04:05Z
2015-05-04T17:04:05Z
2004
Khera, S., M. D. Carducci, J.-Q. Gu, and B. N. Timmermann. "(4R,4aR,6S,7S,7aS)-6-Hydroxy-7-hydroxymethyl-4-methylperhydrocyclopenta[c]pyran-1-one chloroform solvate from Valeriana laxiflora." Acta Cryst. (2004). C60, o773-o775 [http://dx.doi.org./10.1107/S0108270104021511
http://hdl.handle.net/1808/17564
10.1107/S0108270104021511
The structure of an iridolactone isolated from Valeriana laxiflora was established as (4R,4aR,6S,7S,7aS)-6-hydroxy-7-hydroxymethyl-4-methylperhydrocyclopenta[c]pyran-1-one chloroform solvate, C10H16O4·CHCl3. The two rings are cis-fused. The [delta]-lactone ring adopts a slightly twisted half-chair conformation with approximate planarity of the lactone group and the cyclopentane ring adopts an envelope conformation. The hydroxy group, the hydroxymethyl group and the methyl group all have [beta] orientations. The absolute configuration was determined using anomalous dispersion data enhanced by the adventitious inclusion of a chloroform solvent molecule. Hydrogen bonding, crystal packing and ring conformations are discussed in detail.
(4R,4aR,6S,7S,7aS)-6-Hydroxy-7-hy- droxymethyl-4-methylperhydrocyclo- penta[c]pyran-1-one chloroform solvate from Valeriana laxiflora
Article
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URL
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oai:kuscholarworks.ku.edu:1808/134782018-07-13T15:32:06Zcom_1808_100col_1808_101
KU ScholarWorks
author
Visvanathan, Mahesh
author
Siddam, Sasidhar R.
author
Lee, In-Hee
author
Lushington, Gerald H.
author
Bousfield, George R.
2014-04-14T14:48:10Z
2014-04-14T14:48:10Z
2011-04-19
Visvanathan, Mahesh, Sasidhar R Siddam, In-Hee Lee, Gerald H Lushington, and George R Bousfield. 2011. “GlycomicsDB - A Data Integration Platform for Glycans and Their Strucutres.” The Open Medical Informatics Journal 5 : 9–16. http://dx.doi.org/10.2174/1874431101105010009
http://hdl.handle.net/1808/13478
10.2174/1874431101105010009
Glycomics is a discipline of biology that deals with the structure and function of glycans (or carbohydrates). Analytical techniques such as mass spectrometry (MS) and nuclear magnetic resonance (NMR) are having a significant impact on the field of glycomics. However, effective progress in glycomics research requires collaboration between laboratories to share experimental data, structural information of glycans, and simulation results. Herein we report the development of a web-based data management system that can incorporate large volumes of data from disparate sources and organize them into a uniform format for users to store and access. This system enables participating laboratories to set up a shared data repository which members of interdisciplinary teams can access. The system is able to manage and share raw MS data and structural information of glycans.
This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.
Functional glycomics
web-based data management system
Mass spectrometry data
Glycan structure
GlycomicsDB - A Data Integration Platform for Glycans and their Structures
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/13478/1/Visvanathan_et_al_2011.pdf
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oai:kuscholarworks.ku.edu:1808/309372020-12-02T09:00:48Zcom_1808_100col_1808_101
KU ScholarWorks
author
Vilimas, Tomas
author
Wang, Amy Q.
author
Patnaik, Samarjit
author
Hughes, Emma A.
author
Singleton, Marc D.
author
Knotts, Zachary
author
Li, Dandan
author
Frankowski, Kevin
author
Schlomer, Jerome J.
author
Guerin, Theresa M.
author
Springer, Stephanie
author
Drennan, Catherine
author
Dextras, Christopher
author
Wang, Chen
author
Gilbert, Debra
author
Southall, Noel
author
Ferrer, Marc
author
Huang, Sui
author
Kozlov, Serguei
author
Marugan, Juan
author
Xu, Xin
author
Rudloff, Udo
2020-12-01T15:50:18Z
2020-12-01T15:50:18Z
2018-10-10
Vilimas, T., Wang, A. Q., Patnaik, S., Hughes, E. A., Singleton, M. D., Knotts, Z., Li, D., Frankowski, K., Schlomer, J. J., Guerin, T. M., Springer, S., Drennan, C., Dextras, C., Wang, C., Gilbert, D., Southall, N., Ferrer, M., Huang, S., Kozlov, S., Marugan, J., … Rudloff, U. (2018). Pharmacokinetic evaluation of the PNC disassembler metarrestin in wild-type and Pdx1-Cre;LSL-KrasG12D/+;Tp53R172H/+ (KPC) mice, a genetically engineered model of pancreatic cancer. Cancer chemotherapy and pharmacology, 82(6), 1067–1080. https://doi.org/10.1007/s00280-018-3699-0
http://hdl.handle.net/1808/30937
10.1007/s00280-018-3699-0
PMC6267684
Purpose
Metarrestin is a first-in-class small molecule clinical candidate capable of disrupting the perinucleolar compartment, a subnuclear structure unique to metastatic cancer cells. This study aims to define the pharmacokinetic (PK) profile of metarrestin and the pharmacokinetic/pharmacodynamic relationship of metarrestin-regulated markers.
Methods
PK studies included the administration of single or multiple dose of metarrestin at 3, 10, or 25 mg/kg via intravenous (IV) injection, gavage (PO) or with chow to wild-type C57BL/6 mice and KPC mice bearing autochthonous pancreatic tumors. Metarrestin concentrations were analyzed by UPLC–MS/MS. Pharmacodynamic assays included mRNA expression profiling by RNA-seq and qRT-PCR for KPC mice.
Results
Metarrestin had a moderate plasma clearance of 48 mL/min/kg and a large volume of distribution of 17 L/kg at 3 mg/kg IV in C57BL/6 mice. The oral bioavailability after single-dose (SD) treatment was > 80%. In KPC mice treated with SD 25 mg/kg PO, plasma AUC0–∞ of 14400 ng h/mL, Cmax of 810 ng/mL and half-life (t1/2) of 8.5 h were observed. At 24 h after SD of 25 mg/kg PO, the intratumor concentration of metarrestin was high with a mean value of 6.2 µg/g tissue (or 13 µM), well above the cell-based IC50 of 0.4 µM. At multiple dose (MD) 25 mg/kg/day PO in KPC mice, mean tissue/plasma AUC0–24h ratio for tumor, spleen and liver was 37, 30 and 31, respectively. There was a good linear relationship of dosage to AUC0–24h and C24h. AUC0–24h MD to AUC0–24h SD ratios ranged from two for liver to five for tumor indicating additional accumulation in tumors. Dose-dependent normalization of FOXA1 and FOXO6 mRNA expression was observed in KPC tumors.
Conclusions
Metarrestin is an effective therapeutic candidate with a favorable PK profile achieving excellent intratumor tissue levels in a disease with known poor drug delivery.
© The Author(s) 2018
Metarrestin
Peri-nucleolar compartment (PNC)
KPC mice
Pharmacokinetics
Pharmacodynamics
Pharmacokinetic evaluation of the PNC disassembler metarrestin in wild-type and Pdx1-Cre;LSL-KrasG12D/+;Tp53R172H/+ (KPC) mice, a genetically engineered model of pancreatic cancer
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/30937/1/Vilimas_2018.pdf
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oai:kuscholarworks.ku.edu:1808/176612018-07-13T16:47:40Zcom_1808_100col_1808_101
KU ScholarWorks
author
Li, Chengyuan
author
Ma, Jiacheng
author
Zhao, Huiping
author
Blagg, Brian S. J.
author
Dobrowsky, Rick T.
2015-05-08T18:20:19Z
2015-05-08T18:20:19Z
2012-11-01
Li, Chengyuan, Jiacheng Ma, Huiping Zhao, Brian S.J. Blagg, and Rick T. Dobrowsky. "Induction of Heat Shock Protein 70 (Hsp70) prevents Neuregulin-Induced Demyelination by Enhancing the Proteasomal Clearance of c-Jun." ASN Neuro November 2012 vol. 4 no. 7 20120047.
http://dx.doi.org/10.1042/20120047
http://hdl.handle.net/1808/17661
10.1042/20120047
Modulating molecular chaperones is emerging as an attractive approach to treat neurodegenerative diseases associated with protein aggregation, DPN (diabetic peripheral neuropathy) and possibly, demyelinating neuropathies. KU-32 [N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)acetamide] is a small molecule inhibitor of Hsp90 (heat shock protein 90) and reverses sensory deficits associated with myelinated fibre dysfunction in DPN. Additionally, KU-32 prevented the loss of myelinated internodes induced by treating myelinated SC (Schwann cell)-DRG (dorsal root ganglia) sensory neuron co-cultures with NRG1 (neuregulin-1 Type 1). Since KU-32 decreased NRG1-induced demyelination in an Hsp70-dependent manner, the goal of the current study was to clarify how Hsp70 may be mechanistically linked to preventing demyelination. The activation of p42/p44 MAPK (mitogen-activated protein kinase) and induction of the transcription factor c-Jun serve as negative regulators of myelination. NRG1 activated MAPK, induced c-Jun expression and promoted a loss of myelin segments in DRG explants isolated from both WT (wild-type) and Hsp70 KO (knockout) mice. Although KU-32 did not block the activation of MAPK, it blocked c-Jun induction and protected against a loss of myelinated segments in WT mice. In contrast, KU-32 did not prevent the NRG1-dependent induction of c-Jun and loss of myelin segments in explants from Hsp70 KO mice. Overexpression of Hsp70 in myelinated DRG explants prepared from WT or Hsp70 KO mice was sufficient to block the induction of c-Jun and the loss of myelin segments induced by NRG1. Lastly, inhibiting the proteasome prevented KU-32 from decreasing c-Jun levels. Collectively, these data support that Hsp70 induction is sufficient to prevent NRG1-induced demyelination by enhancing the proteasomal degradation of c-Jun.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.
Diabetic neuropathy
Molecular chaperones
Myelin basic protein
Schwann cells
Sensory neurons
Induction of Heat Shock Protein 70 (Hsp70) prevents Neuregulin-Induced Demyelination by Enhancing the Proteasomal Clearance of c-Jun
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/17661/1/BlaggB_ASNN_4%287%29425.pdf
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oai:kuscholarworks.ku.edu:1808/332062022-08-16T08:01:38Zcom_1808_100col_1808_101
KU ScholarWorks
author
Chilamari, Maheshwerreddy
author
Immel, Jacob R.
author
Chen, Pei-Hsuan
author
Alghafli, Bayan M.
author
Bloom, Steven
2022-08-15T18:14:09Z
2022-08-15T18:14:09Z
2022-03-22
Chilamari, M., Immel, J. R., Chen, P. H., Alghafli, B. M., & Bloom, S. (2022). Flavin Metallaphotoredox Catalysis: Synergistic Synthesis in Water. ACS catalysis, 12(7), 4175–4181. https://doi.org/10.1021/acscatal.2c00773
http://hdl.handle.net/1808/33206
10.1021/acscatal.2c00773
https://orcid.org/0000-0002-4205-4459
35865831
Combining a transition metal with a photocatalyst can drive modern synthetic chemistry. For transformations performed in water, this concept has been largely unexplored. We report the successful merger of a biocompatible flavin photocatalyst with a palladium catalyst to build isotopically enriched peptidomimetics, to mediate conjugate addition and C–H functionalization reactions, and to assemble unprotected proteinogenic and nonproteinogenic peptides, in water. We detail the important role of the ligand and the palladium oxidation state for controlling product selectivity when constructing synthetic peptides.
Copyright © 2022 American Chemical Society
Metallaphotoredox
Flavin
Boronic acids
Biocompatible
Isotopes
Peptidomimetics
Flavin Metallaphotoredox Catalysis: Synergistic Synthesis in Water
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/33206/1/Chilamari_2022.pdf
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oai:kuscholarworks.ku.edu:1808/176542019-04-12T14:22:15Zcom_1808_100col_1808_101
KU ScholarWorks
author
Balakrishna, Rajalakshmi
author
Wood, Stewart J.
author
Nguyen, Thuan B.
author
Miller, Kelly A.
author
Kumar, E. V. K. Suresh
author
Datta, Apurba
author
David, Sunil A.
2015-05-07T21:20:16Z
2015-05-07T21:20:16Z
2006-03
Balakrishna et. al. "Structural Correlates of Antibacterial and Membrane-Permeabilizing Activities in Acylpolyamines."
Antimicrob. Agents Chemother. March 2006 vol. 50 no. 3 852-861 .
http://dx.doi.org/10.1128/AAC.50.3.852-861.2006
http://hdl.handle.net/1808/17654
10.1128/AAC.50.3.852-861.2006
A homologous series of mono- and bis-acyl polyamines with varying acyl chain lengths originally synthesized for the purpose of sequestering lipopolysaccharide were evaluated for antimicrobial activity to test the hypothesis that these bis-cationic amphipathic compounds may also bind to and permeabilize intact gram-negative bacterial membranes. Some compounds were found to possess significant antimicrobial activity, mediated via permeabilization of bacterial membranes. Structure-activity relationship studies revealed a strong dependence of the acyl chain length on antimicrobial potency and permeabilization activity. Homologated spermine, bis-acylated with C8 or C9 chains, was found to profoundly sensitize Escherichia coli to hydrophobic antibiotics such as rifampin. Nonspecific cytotoxicity is a potential drawback of these membranophilic compounds. However, the surface activity of these cationic amphipaths is strongly attenuated under physiological conditions via binding to serum albumin. Significant antibacterial activity is still retained in the presence of physiological concentrations of human serum albumin, suggesting that these compounds may serve as leads in the development of novel adjuncts to conventional antimicrobial chemotherapy.
Structural Correlates of Antibacterial and Membrane-Permeabilizing Activities in Acylpolyamines
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/17654/1/DavidS_DuttaA_AAC_50%283%29852.pdf
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oai:kuscholarworks.ku.edu:1808/238332019-04-12T14:15:57Zcom_1808_100col_1808_101
KU ScholarWorks
author
Ma, Jiacheng
author
Pan, Pan
author
Anyika, Mercy
author
Blagg, Brian S. J.
author
Dobrowsky, Rick T.
2017-04-27T16:46:49Z
2017-04-27T16:46:49Z
2015-09-16
Ma, J., Pan, P., Anyika, M., Blagg, B. S. J., & Dobrowsky, R. T. (2015). Modulating Molecular Chaperones Improves Mitochondrial Bioenergetics and Decreases the Inflammatory Transcriptome in Diabetic Sensory Neurons. ACS Chemical Neuroscience, 6(9), 1637–1648. http://doi.org/10.1021/acschemneuro.5b00165
http://hdl.handle.net/1808/23833
10.1021/acschemneuro.5b00165
https://orcid.org/0000-0002-9573-9443
PMC4573952
We have previously demonstrated that modulating molecular chaperones with KU-32, a novobiocin derivative, ameliorates physiologic and bioenergetic deficits of diabetic peripheral neuropathy (DPN). Replacing the coumarin core of KU-32 with a meta-fluorinated biphenyl ring system created KU-596, a novobiocin analogue (novologue) that showed neuroprotective activity in a cell-based assay. The current study sought to determine whether KU-596 offers similar therapeutic potential for treating DPN. Administration of 2–20 mg/kg of KU-596 improved diabetes induced hypoalgesia and sensory neuron bioenergetic deficits in a dose-dependent manner. However, the drug could not improve these neuropathic deficits in diabetic heat shock protein 70 knockout (Hsp70 KO) mice. To gain further insight into the mechanisms by which KU-596 improved DPN, we performed transcriptomic analysis of sensory neuron RNA obtained from diabetic wild-type and Hsp70 KO mice using RNA sequencing. Bioinformatic analysis of the differentially expressed genes indicated that diabetes strongly increased inflammatory pathways and that KU-596 therapy effectively reversed these increases independent of Hsp70. In contrast, the effects of KU-596 on decreasing the expression of genes regulating the production of reactive oxygen species were more Hsp70-dependent. These data indicate that modulation of molecular chaperones by novologue therapy offers an effective approach toward correcting nerve dysfunction in DPN but that normalization of inflammatory pathways alone by novologue therapy seems to be insufficient to reverse sensory deficits associated with insensate DPN.
Copyright © 2015 American Chemical Society
Bioenergetics
Diabetic neuropathy
Inflammation
Molecular chaperones
Oxidative stress
RNA Seq
Modulating Molecular Chaperones Improves Mitochondrial Bioenergetics and Decreases the Inflammatory Transcriptome in Diabetic Sensory Neurons
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23833/1/Ma_ACS_2015.pdf
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oai:kuscholarworks.ku.edu:1808/243892019-04-12T14:18:41Zcom_1808_100col_1808_101
KU ScholarWorks
author
Guttman, Miklos
author
Weis, David D.
author
Engen, John R.
author
Lee, Kelly K.
2017-06-06T19:13:02Z
2017-06-06T19:13:02Z
2013-12
Guttman, M., Weis, D. D., Engen, J. R., & Lee, K. K. (2013). Analysis of Overlapped and Noisy Hydrogen/Deuterium Exchange Mass Spectra. Journal of the American Society for Mass Spectrometry, 24(12), 10.1007/s13361–013–0727–5. http://doi.org/10.1007/s13361-013-0727-5
http://hdl.handle.net/1808/24389
10.1007/s13361-013-0727-5
PMC3855366
Noisy and overlapped mass spectrometry data hinders the sequence coverage that can be obtained from Hydrogen Deuterium exchange analysis, and places a limit on the complexity of the samples that can be studied by this technique. Advances in instrumentation have addressed these limits, but as the complexity of the biological samples under investigation increases, these problems are reencountered. Here we describe the use of binomial distribution fitting with asymmetric linear squares regression for calculating the accurate deuterium content for mass envelopes of low signal or that contain significant overlap. The approach is demonstrated with a test data set of HIV Env gp140 wherein inclusion of the new analysis regime resulted in obtaining exchange data for 42 additional peptides, improving the sequence coverage by 11%. At the same time, the precision of deuterium uptake measurements was improved for nearly every peptide examined. The improved processing algorithms also provide an efficient method for deconvolution of bimodal mass envelopes and EX1 kinetic signatures. All these functions and visualization tools have been implemented in the new version of the freely available software, HX-Express v2.
Analysis of Overlapped and Noisy Hydrogen/Deuterium Exchange Mass Spectra
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/24389/2/Guttman_2013.pdf
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oai:kuscholarworks.ku.edu:1808/235022019-04-12T14:25:14Zcom_1808_100col_1808_101
KU ScholarWorks
author
Comer, Shawna B.
author
Vielhauer, George A.
author
Manthe, Craig A.
author
Chaguturu, Vamsee K.
author
Szabla, Kristen
author
Matts, Robert L.
author
Donnelly, Alison C.
author
Blagg, Brian S. J.
author
Holzbeierlein, Jeffery M.
2017-03-28T18:29:03Z
2017-03-28T18:29:03Z
2010-01-01
Shawna, B. C., George, A. V., Craig, A. M., Vamsee, K. C., Kristen, S., Robert, L. M., … Jeffrey, M. H. (2010). Characterization of a novel novobiocin analogue as a putative C-terminal inhibitor of heat shock protein 90 in prostate cancer cells. The Prostate, 70(1), 27–36. http://doi.org/10.1002/pros.21035
http://hdl.handle.net/1808/23502
10.1002/pros.21035
PURPOSE: Hsp90 is important in the folding, maturation and stabilization of pro-tumorigenic client proteins and represents a viable drug target for the design of chemotherapies. Previously, we reported the development of novobiocin analogues designed to inhibit the C-terminal portion of Hsp90, which demonstrated the ability to decrease client protein expression. We now report the characterization of the novel novobiocin analogue, F-4, which demonstrates improved cytotoxicity in prostate cancer cell lines compared to the N-terminal inhibitor, 17-AAG. MATERIALS AND METHODS: LNCaP and PC-3 cells were treated with 17-AAG or F-4 in anti-proliferative, apoptosis, cell cycle and cytotoxicity assays. Western blot and prostate specific antigen (PSA) ELISAs were used to determine client protein degradation, induction of Hsp90 and to assess the functional status of the androgen receptor (AR) in response to F-4 treatment. Surface Plasmon Resonance (SPR) was also used to determine the binding properties of F-4 to Hsp90. RESULTS: F-4 demonstrated improved potency and efficacy compared to novobiocin in anti-proliferative assays and decreased expression of client proteins. PSA secretion was inhibited in a dose-dependent manner that paralleled a decrease in AR expression. The binding of F-4 to Hsp90 was determined to be saturable with a binding affinity (Kd) of 100 µM. In addition, superior efficacy was demonstrated by F-4 compared to 17-AAG in experiments measuring cytotoxicity and apoptosis. CONCLUSIONS: These data reveal distinct modes of action for N-terminal and C-terminal Hsp90 inhibitors, which may offer unique therapeutic benefits for the treatment of prostate cancer.
This is the peer reviewed version of the following article: Prostate, which has been published in final form at http://dx.doi.org/10.1002/pros.21035. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Hsp90 inhibitors
Prostate cancer
Novobiocin
Characterization of a novel novobiocin analogue as a putative Cterminal inhibitor of heat shock protein 90 in prostate cancer cells
Article
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URL
https://kuscholarworks.ku.edu/bitstream/1808/23502/1/Donnelly_2010.pdf
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Donnelly_2010.pdf
URL
https://kuscholarworks.ku.edu/bitstream/1808/23502/3/Donnelly_2010.pdf.txt
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Donnelly_2010.pdf.txt
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