Thursday, October 11, 2012
Targeting the full-length HCV NS3/4A protein complex. Researchers at Astex Pharmaceuticals Inc.
have identified a new binding pocket on the full-length HCV NS3/4A protein
complex that could be targeted to treat HCV infection. The full-length protein
consists of a helicase domain linked to a protease domain.
The complex switches between an active, open conformation and an inactive,
closed conformation. In the closed conformation, the C-terminus of the helicase
domain occupies the protease active site.
Direct inhibition of the protease active site is the primary strategy drug
developers have pursued to inhibit the complex. There are already at least 2
such drugs marketed to treat HCV infection and at least another 10 in clinical
trials. Targeting this site inhibits the complex's proteolytic activity [II(a)].
identified allosteric site is present when the full-length NS3/4A protein
complex is in its closed conformation. Compounds that target the site stabilize
the complex in this inactive conformation [II(b)]. Unlike inhibitors
against the protease active site, compounds that target the allosteric site
also have the potential to inhibit the complex's helicase activity in addition
to its proteolytic activity.