Structure-activity relationships in toll-like receptor 2-agonists leading to simplified monoacyl lipopeptides

Geetanjali Agnihotri, Breanna M. Crall, Tyler C. Lewis, Timothy P. Day, Rajalakshmi Balakrishna, Hemamali J. Warshakoon, Subbalakshmi S. Malladi, Sunil A. David

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41 Scopus citations

Abstract

Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM 2CS) 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 (C 16) and an appropriately oriented 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.

Original languageEnglish (US)
Pages (from-to)8148-8160
Number of pages13
JournalJournal of medicinal chemistry
Volume54
Issue number23
DOIs
StatePublished - Dec 8 2011

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    Agnihotri, G., Crall, B. M., Lewis, T. C., Day, T. P., Balakrishna, R., Warshakoon, H. J., Malladi, S. S., & 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. https://doi.org/10.1021/jm201071e