Hepatitis C virus (HCV) is a disease that has a growing impact worldwide. A combination therapy comprising interferon-alpha (IFNalpha) and ribavirin represents the current standard treatment for chronic HCV infection, although it has demonstrated limited success and causes some serious side effects. Promising alternative approaches toward the control of HCV infection, and the development of new antiviral agents, include the use of NS3/4A serine protease and NS5B polymerase inhibitors. Successful proof-of-concept clinical trials of the NS3/4A protease inhibitor BILN-2061 have confirmed the usefulness of a peptidomimetic product-based approach, providing impetus for the generation of improved molecules. Preclinical results from the development of HCV polymerase inhibitors, both nucleoside and non-nucleoside, are promising. This review provides an overview of recent progress in these areas, and discusses the potential of various approaches toward small molecule HCV antivirals.
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