Non-nucleoside inhibitors of hepatitis C virus polymerase: current progress and future challenges

The current standard of care for hepatitis C virus (HCV) infection is a combination of PEGylated interferon and ribavirin, which offer limited efficacy and significant side effects. Novel HCV-specific inhibitors, including those directed at the viral polymerase, have become the focus of HCV drug-discovery efforts in the past decade. In addition to the active site targeted by traditional nucleoside inhibitors, at least four different allosteric-binding sites have been reported for the HCV polymerase, which offer ample opportunities for small-molecule inhibitors. In this review, we summarize the recent progress in the discovery of non-nucleoside HCV polymerase inhibitors with a focus on novel chemical matters, their clinical efficacy, safety and potential for combination therapy.