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Structure-Activity Relationships in Human Toll-like Receptor 2- Specific Monoacyl Lipopeptides
Salunke, Deepak B. Shukla, Nikunj M. Yoo, Euna Crall, Breanna M. Balakrishna, Rajalakshmi Malladi, Subbalakshmi S. David, Sunil A.
Salunke, Deepak B.
Shukla, Nikunj M.
Yoo, Euna
Crall, Breanna M.
Balakrishna, Rajalakshmi
Malladi, Subbalakshmi S.
David, Sunil A.
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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. 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.
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Date
2012-04-12
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American Chemical Society
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Keywords
TLR2, TLR2 agonists, Vaccine adjuvants, Innate immunity, Lipopeptides
Citation
Salunke, D. B., Shukla, N. M., Yoo, E., Crall, B. M., Balakrishna, R., Malladi, S. S., & David, S. A. (2012). Structure-Activity Relationships in Human Toll-like Receptor 2-Specific Monoacyl Lipopeptides. Journal of Medicinal Chemistry, 55(7), 3353–3363. http://doi.org/10.1021/jm3000533