Structure鈥揂ctivity Relationships in Toll-Like Receptor 2-Agonists Leading to Simplified Monoacyl Lipopeptides

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• 作者：Geetanjali Agnihotri ; Breanna M. Crall ; Tyler C. Lewis ; Timothy P. Day ; Rajalakshmi Balakrishna ; Hemamali J. Warshakoon ; Subbalakshmi S. Malladi ; Sunil A. David
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 8, 2011
• 年：2011
• 卷：54
• 期：23
• 页码：8148-8160
• 全文大小：853K
• 年卷期：v.54,no.23(December 8, 2011)
• ISSN：1520-4804

文摘

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鈥揳ctivity relationships on this chemotype, we have determined that at least one acyl group of optimal length (C₁₆) 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.