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JAC Advance Access published online on June 9, 2004
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh319
© 2004 by The British Society for Antimicrobial Chemotherapy
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Leading article

Non-nucleoside inhibitors of the HCV polymerase

Robert T. Sarisky 1*

1 Department of Virology, The Metabolic and Viral Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, Collegeville, PA 19426, USA

* To whom correspondence should be addressed. E-mail: rsarisky{at}cntus.jnj.com.


  Abstract

Chronic hepatitis C virus (HCV) infection is the leading cause of chronic liver disease. Current therapy using pegylated interferon-{alpha} with ribavirin is poorly tolerated and confers an overall sustained virological response around 56%. Compounds exhibiting an improved safety profile with similar or enhanced antiviral properties may represent future treatment options. Several drug discovery programmes are ongoing to directly target the viral enzymes involved in HCV replication. Recent clinical success using a peptidomimetic inhibitor of the viral serine protease has demonstrated proof-of-concept for the use of direct antiviral agents in reducing viral load. The RNA-dependent RNA polymerase (RdRp) of HCV is also required for viral RNA replication and thus represents an attractive drug discovery target. Preclinical characterization of several non-nucleoside inhibitors (NNIs) of the HCV RdRp have been described, including a promising series of benzothiadiazine derivatives which have been shown to efficiently block viral RNA synthesis in HCV replicon cell systems. Herein, the antiviral activity, mode of action, resistance profiling and therapeutic potential of the benzothiadiazine class of compounds for clinical development are explored.

Key Words: Keywords: benzothiadiazines, NS5B, IFN-{alpha}, RdRp inhibitors


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