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


ABSTRACT: Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM(2)CS) 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.

SUBMITTER: Agnihotri G 

PROVIDER: S-EPMC3228886 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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

Agnihotri Geetanjali G   Crall Breanna M BM   Lewis Tyler C TC   Day Timothy P TP   Balakrishna Rajalakshmi R   Warshakoon Hemamali J HJ   Malladi Subbalakshmi S SS   David Sunil A SA  

Journal of medicinal chemistry 20111104 23


Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM(2)CS) 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 thioethe  ...[more]

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