Show simple item record

dc.contributor.authorAgnihotri, Geetanjali
dc.contributor.authorCrall, Breanna M.
dc.contributor.authorLewis, Tyler C.
dc.contributor.authorDay, Timothy P.
dc.contributor.authorBalakrishna, Rajalakshmi
dc.contributor.authorWarshakoon, Hemamali J.
dc.contributor.authorMalladi, Subbalakshmi S.
dc.contributor.authorDavid, Sunil A.
dc.identifier.citationAgnihotri, 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.
dc.description.abstractToll-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.en_US
dc.publisherAmerican Chemical Societyen_US
dc.rightsThis 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
dc.subjectTLR2 agonistsen_US
dc.subjectVaccine adjuvantsen_US
dc.subjectInnate immunityen_US
dc.titleStructure-Activity Relationships in Toll-like Receptor 2-Agonists Leading to Simplified Monoacyl Lipopeptidesen_US
kusw.kuauthorAgnihotri, Geetanjali
kusw.kuauthorCrall, Breanna M.
kusw.kuauthorLewis, Tyler C.
kusw.kuauthorDay, Timothy P.
kusw.kuauthorBalakrishna, Rajalakshmi
kusw.kuauthorWarshakoon, Hemamali J.
kusw.kuauthorMalladi, Subbalakshmi S.
kusw.kuauthorDavid, Sunil A.
kusw.kudepartmentMedicinal Chemistryen_US
kusw.oanotesPer SHERPA/RoMEO 4/12/2017: Author's Pre-print: grey tick subject to Restrictions below, author can archive pre-print (ie pre-refereeing) Restrictions:

Must obtain written permission from Editor Must not violate ACS ethical Guidelines

Author's Post-print: grey tick subject to Restrictions below, author can archive post-print (ie final draft post-refereeing) Restrictions:

If mandated by funding agency or employer/ institution If mandated to deposit before 12 months, must obtain waiver from Institution/Funding agency or use AuthorChoice 12 months embargo

Publisher's Version/PDF: cross author cannot archive publisher's version/PDF
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US

Files in this item


This item appears in the following Collection(s)

Show simple item record