Finger loop inhibitors of the HCV NS5B polymerase: discovery and prospects for new HCV therapy

Abstract

The hepatitis C virus (HCV) infects millions of people wzorldwzide and currently available therapies suffer from limited efficacy and severe side effects. This review describes the discovery of a novel class of non-nucleoside HCV non-structural protein 5B (NS5B) polymerase inhibitors that inhibit the replication of viral RNA by binding to an allosteric site on the enzyme. Initial lead compounds based on a benzimidazole scaffold were optimized yielding novel indole derivatives with sub-micromolar activity in a cell-based replicon assay. X-ray crystallographic studies suggest that inhibitor binding interferes with the conformational movements of the protein that are necessary for enzyme activity. Finger loop inhibitors of HCV NS5B show potential for the development of novel anti-HCV therapeutics.