Structure鈥揂ctivity Relationships in Human Toll-like Receptor 2-Specific Monoacyl Lipopeptides

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• 作者：Deepak B. Salunke ; Nikunj M. Shukla ; Euna Yoo ; Breanna M. Crall ; Rajalakshmi Balakrishna ; Subbalakshmi S. Malladi ; Sunil A. David
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 12, 2012
• 年：2012
• 卷：55
• 期：7
• 页码：3353-3363
• 全文大小：394K
• 年卷期：v.55,no.7(April 12, 2012)
• 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. We had previously determined that at least one acyl group of optimal length (C₁₆) and an appropriately orientated ester carbonyl group is essential for TLR2-agonistic activity. We now show that these structurally simpler analogues display agonistic activities with human, but not murine, TLR2. SAR studies on the monoacyl derivatives show that the optimal acyl chain length is C₁₆, and aryl substituents are not tolerated. A variety of alkyl and acyl substituents on the cysteine amine were examined. All N-alkyl derivatives were inactive. In contradistinction, short-chain N-acyl analogues were found to be highly active, with a clear dependence on the chain length. A cysteine N-acetyl analogue was found to be the most potent (EC₅₀: 1 nM), followed by the N-butyryl analogue. The N-acetyl analogue is human TLR2-specific, with its potency comparable to that of PAM₂CS.