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Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect

Author

Listed:
  • Min Gao

    (Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA)

  • Richard E. Nettles

    (Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, USA)

  • Makonen Belema

    (Department of Discovery Chemistry,)

  • Lawrence B. Snyder

    (Department of Discovery Chemistry,)

  • Van N. Nguyen

    (Department of Discovery Chemistry,)

  • Robert A. Fridell

    (Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA)

  • Michael H. Serrano-Wu

    (Department of Discovery Chemistry,)

  • David R. Langley

    (Department of Computer-Aided Drug Design,)

  • Jin-Hua Sun

    (Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA)

  • Donald R. O’Boyle II

    (Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA)

  • Julie A. Lemm

    (Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA)

  • Chunfu Wang

    (Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA)

  • Jay O. Knipe

    (Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA)

  • Caly Chien

    (Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, USA)

  • Richard J. Colonno

    (Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA)

  • Dennis M. Grasela

    (Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, USA)

  • Nicholas A. Meanwell

    (Department of Discovery Chemistry,)

  • Lawrence G. Hamann

    (Department of Discovery Chemistry,)

Abstract

New drugs for hepatitis C The development of direct-acting antiviral agents to treat chronic hepatitis C virus (HCV) infection, much needed clinically, has focused largely on inhibitors of two viral enzymes, the protease NS3 and NS5B, an RNA-dependent RNA polymerase essential for HCV replication. BMS-790052, identified using chemical genetics as a powerful specific HCV inhibitor, is a small-molecule inhibitor of a third viral molecule that has no known enzyme activity, the non-structural protein 5A (NS5A). A research team from Bristol-Myers Squibb this week reports on the discovery and virological profile of BMS-790052 and discloses clinical trial observations with this compound in normal healthy volunteers and HCV-infected subjects. These results establish proof-of-concept for HCV NS5A inhibition as a clinically relevant mechanism. In vitro data point to synergistic interactions with known HCV inhibitors, suggesting that cocktails of antiviral agents may be a viable therapeutic approach.

Suggested Citation

  • Min Gao & Richard E. Nettles & Makonen Belema & Lawrence B. Snyder & Van N. Nguyen & Robert A. Fridell & Michael H. Serrano-Wu & David R. Langley & Jin-Hua Sun & Donald R. O’Boyle II & Julie A. Lemm &, 2010. "Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect," Nature, Nature, vol. 465(7294), pages 96-100, May.
    • Handle: RePEc:nat:nature:v:465:y:2010:i:7294:d:10.1038_nature08960
    DOI: 10.1038/nature08960
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    Cited by:

    1. Libin Rong & Jeremie Guedj & Harel Dahari & Daniel J Coffield Jr & Micha Levi & Patrick Smith & Alan S Perelson, 2013. "Analysis of Hepatitis C Virus Decline during Treatment with the Protease Inhibitor Danoprevir Using a Multiscale Model," PLOS Computational Biology, Public Library of Science, vol. 9(3), pages 1-12, March.
    2. Dominik Kiemel & Ann-Sophie Helene Kroell & Solène Denolly & Uta Haselmann & Jean-François Bonfanti & Jose Ignacio Andres & Brahma Ghosh & Peggy Geluykens & Suzanne J. F. Kaptein & Lucas Wilken & Piet, 2024. "Pan-serotype dengue virus inhibitor JNJ-A07 targets NS4A-2K-NS4B interaction with NS2B/NS3 and blocks replication organelle formation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Tiffany Benzine & Ryan Brandt & William C Lovell & Daisuke Yamane & Petra Neddermann & Raffaele De Francesco & Stanley M Lemon & Alan S Perelson & Ruian Ke & David R McGivern, 2017. "NS5A inhibitors unmask differences in functional replicase complex half-life between different hepatitis C virus strains," PLOS Pathogens, Public Library of Science, vol. 13(6), pages 1-20, June.

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