Quinolones as HCV NS5B polymerase inhibitors

Dange V. Kumar, Roopa Rai, Ken A. Brameld, John R. Somoza, Ravi Rajagopalan, James W. Janc, Yu M. Xia, Tony L. Ton, Michael B. Shaghafi, Huiyong Hu, Isabelle Lehoux, Nhat To, Wendy B. Young, Michael J. Green

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Hepatitis C virus (HCV) infection is treated with a combination of peginterferon alfa-2a/b and ribavirin. To address the limitations of this therapy, numerous small molecule agents are in development, which act by directly affecting key steps in the viral life-cycle. Herein we describe our discovery of quinolone derivatives, novel small-molecules that inhibit NS5b polymerase, a key enzyme of the viral life-cycle. A crystal structure of a quinoline analog bound to NS5B reveals that this class of compounds binds to allosteric site-II (non-nucleoside inhibitor-site 2, NNI-2) of this protein.

Original languageEnglish (US)
Pages (from-to)82-87
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number1
DOIs
StatePublished - Jan 1 2011

Keywords

  • Cocrystal structure
  • HCV
  • HCV NS5B NNI-2 binder
  • Non-nucleoside inhibitors
  • NS5B polymerase inhibitors
  • Quinolone derivatives

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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  • Cite this

    Kumar, D. V., Rai, R., Brameld, K. A., Somoza, J. R., Rajagopalan, R., Janc, J. W., Xia, Y. M., Ton, T. L., Shaghafi, M. B., Hu, H., Lehoux, I., To, N., Young, W. B., & Green, M. J. (2011). Quinolones as HCV NS5B polymerase inhibitors. Bioorganic and Medicinal Chemistry Letters, 21(1), 82-87. https://doi.org/10.1016/j.bmcl.2010.11.068