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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.date.accessioned2017-04-12T14:37:01Z
dc.date.available2017-04-12T14:37:01Z
dc.date.issued2011-12-08
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. http://doi.org/10.1021/jm201071een_US
dc.identifier.urihttp://hdl.handle.net/1808/23626
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 http://dx.doi.org/10.1021/jm201071e.en_US
dc.subjectTLR2en_US
dc.subjectTLR2 agonistsen_US
dc.subjectVaccine adjuvantsen_US
dc.subjectInnate immunityen_US
dc.subjectLipopeptidesen_US
dc.titleStructure-Activity Relationships in Toll-like Receptor 2-Agonists Leading to Simplified Monoacyl Lipopeptidesen_US
dc.typeArticleen_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
dc.identifier.doi10.1021/jm201071een_US
dc.identifier.orcidhttps://orcid.org/0000-0003-2197-1917
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.rights.accessrightsopenAccess


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