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Mechanism of Action of Direct-Acting Antivirals: New Insights into the HCV Life Cycle

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Hepatitis C Virus II

Abstract

The urgent need for novel therapeutics to address the burden of disease associated with chronic hepatitis C has driven the development of direct-acting antivirals (DAA) that target hepatitis C virus (HCV) replication. Combination therapies targeting multiple viral proteins can increase the genetic barrier to resistance, and all-oral, interferon-free regimens combining different classes of DAA are proving highly effective in treating chronic hepatitis C. Most if not all HCV nonstructural proteins are multifunctional and act in concert with viral and cellular interaction partners in macromolecular complexes. As a consequence, inhibitors that target a single HCV protein can impact several different stages in the HCV life cycle. Studies designed to understand how DAAs act on the functions of individual HCV proteins at the molecular level have provided novel insights into the viral replicase complex, viral RNA synthesis, and virion assembly. DAAs currently used in the clinic include inhibitors that target the NS3/4A protease, the NS5A protein, and the NS5B RNA-dependent RNA polymerase. This review will discuss the mode of action of each of the major classes of antiviral drugs and how they interrupt the HCV life cycle at the molecular level.

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Acknowledgements

Supported in part by grants from the National Institutes of Health R21-AI115207 (DRM), T32-AI007151 (SEW) and the University Cancer Research Fund of the University of North Carolina.

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  1. Division of Infectious Diseases, Department of Medicine and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7295, USA

    Sara E. Williford & David R. McGivern

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  1. Sara E. Williford
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  2. David R. McGivern
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Correspondence to David R. McGivern .

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Editors and Affiliations

  1. National Institute of Infectious Disease , Tokyo, Japan

    Tatsuo Miyamura

  2. Departments of Medicine and Microbiology, The Univ of N Carolina at Chapel Hill Departments of Medicine and Microbiology, Chapel Hill, North Carolina, USA

    Stanley M. Lemon

  3. Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital , Ohio, USA

    Christopher M. Walker

  4. National Institute of Infectious Disease, Tokyo, Japan

    Takaji Wakita

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Williford, S.E., McGivern, D.R. (2016). Mechanism of Action of Direct-Acting Antivirals: New Insights into the HCV Life Cycle. In: Miyamura, T., Lemon, S., Walker, C., Wakita, T. (eds) Hepatitis C Virus II. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56101-9_11

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