A survey of isosteric replacements of the phosphonoalanine side chain coupl
ed with a process of conformational constraint of a bisbenzimidazole-based,
Zn2+-dependent inhibitor of hepatitis C virus (HCV) NS3 serine protease re
sulted in the identification of novel series of active compounds with exten
ded side chains. However, Zn2+-dependent HCV NS3 inhibition was relatively
insensitive to the structural variations examined but dependent on the pres
ence of negatively charged functionality. This result was interpreted in th
e context of an initial electrostatic interaction between protease and inhi
bitor that is subsequently consolidated by Zn2+, with binding facilitated b
y the featureless active site and proximal regions of the HCV NS3 protein.
(C) 2001 Elsevier Science Ltd. All rights reserved.