Figure 1. 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.

[I] 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.

[II] 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)].

The newly 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.