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Structure-Activity Relationships in Toll-like Receptor 2-Agonists Leading to Simplified Monoacyl Lipopeptides
dc.contributor.author | Agnihotri, Geetanjali | |
dc.contributor.author | Crall, Breanna M. | |
dc.contributor.author | Lewis, Tyler C. | |
dc.contributor.author | Day, Timothy P. | |
dc.contributor.author | Balakrishna, Rajalakshmi | |
dc.contributor.author | Warshakoon, Hemamali J. | |
dc.contributor.author | Malladi, Subbalakshmi S. | |
dc.contributor.author | David, Sunil A. | |
dc.date.accessioned | 2017-04-12T14:37:01Z | |
dc.date.available | 2017-04-12T14:37:01Z | |
dc.date.issued | 2011-12-08 | |
dc.identifier.citation | 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 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/23626 | |
dc.description.abstract | 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. | en_US |
dc.publisher | American Chemical Society | en_US |
dc.rights | 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. | en_US |
dc.subject | TLR2 | en_US |
dc.subject | TLR2 agonists | en_US |
dc.subject | Vaccine adjuvants | en_US |
dc.subject | Innate immunity | en_US |
dc.subject | Lipopeptides | en_US |
dc.title | Structure-Activity Relationships in Toll-like Receptor 2-Agonists Leading to Simplified Monoacyl Lipopeptides | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Agnihotri, Geetanjali | |
kusw.kuauthor | Crall, Breanna M. | |
kusw.kuauthor | Lewis, Tyler C. | |
kusw.kuauthor | Day, Timothy P. | |
kusw.kuauthor | Balakrishna, Rajalakshmi | |
kusw.kuauthor | Warshakoon, Hemamali J. | |
kusw.kuauthor | Malladi, Subbalakshmi S. | |
kusw.kuauthor | David, Sunil A. | |
kusw.kudepartment | Medicinal Chemistry | en_US |
dc.identifier.doi | 10.1021/jm201071e | en_US |
dc.identifier.orcid | https://orcid.org/0000-0003-2197-1917 | |
kusw.oaversion | Scholarly/refereed, author accepted manuscript | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.rights.accessrights | openAccess |