TY - JOUR
T1 - Structure-activity relationships in human toll-like receptor 2-specific monoacyl lipopeptides
AU - Salunke, Deepak B.
AU - Shukla, Nikunj M.
AU - Yoo, Euna
AU - Crall, Breanna M.
AU - Balakrishna, Rajalakshmi
AU - Malladi, Subbalakshmi S.
AU - David, Sunil A.
PY - 2012/4/12
Y1 - 2012/4/12
N2 - Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM 2CS) compounds are potential vaccine adjuvants. We had previously determined that at least one acyl group of optimal length (C 16) 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 C 16, 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 (EC 50: 1 nM), followed by the N-butyryl analogue. The N-acetyl analogue is human TLR2-specific, with its potency comparable to that of PAM 2CS.
AB - Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM 2CS) compounds are potential vaccine adjuvants. We had previously determined that at least one acyl group of optimal length (C 16) 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 C 16, 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 (EC 50: 1 nM), followed by the N-butyryl analogue. The N-acetyl analogue is human TLR2-specific, with its potency comparable to that of PAM 2CS.
UR - http://www.scopus.com/inward/record.url?scp=84859802144&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84859802144&partnerID=8YFLogxK
U2 - 10.1021/jm3000533
DO - 10.1021/jm3000533
M3 - Article
C2 - 22385476
AN - SCOPUS:84859802144
SN - 0022-2623
VL - 55
SP - 3353
EP - 3363
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 7
ER -