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Structure-Activity Relationships in Toll-like Receptor 2-Agonists Leading to Simplified Monoacyl Lipopeptides
Agnihotri, Geetanjali Crall, Breanna M. Lewis, Tyler C. Day, Timothy P. Balakrishna, Rajalakshmi Warshakoon, Hemamali J. Malladi, Subbalakshmi S. David, Sunil A.
Agnihotri, Geetanjali
Crall, Breanna M.
Lewis, Tyler C.
Day, Timothy P.
Balakrishna, Rajalakshmi
Warshakoon, Hemamali J.
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. 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.
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2011-12-08
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American Chemical Society
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Crall_2011.pdf
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TLR2, TLR2 agonists, Vaccine adjuvants, Innate immunity, Lipopeptides
Citation
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