Structure-Activity Relationships in Toll-like Receptor 2-Agonists Leading to Simplified Monoacyl Lipopeptides
Crall, Breanna M.
Lewis, Tyler C.
Day, Timothy P.
Warshakoon, Hemamali J.
Malladi, Subbalakshmi S.
David, Sunil A.
American Chemical Society
Scholarly/refereed, author accepted manuscript
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.
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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.
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
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