jm201071e_si_001.pdf (8.56 MB)
Structure–Activity Relationships in Toll-Like Receptor 2-Agonists Leading to Simplified Monoacyl Lipopeptides
journal contribution
posted on 2011-12-08, 00:00 authored by Geetanjali Agnihotri, Breanna M. Crall, Tyler C. Lewis, Timothy P. Day, Rajalakshmi Balakrishna, Hemamali J. Warshakoon, Subbalakshmi S. Malladi, Sunil A. DavidToll-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 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.