Characterization of the Inhibition of Hepatitis C Virus RNA Replication by Nonnucleosides

Licia Tomei, Sergio Altamura, Linda Bartholomew, Monica Bisbocci, Carolyn Bailey, Michele Bosserman, Antonella Cellucci, Eleonora Forte, Ilario Incitti, Laura Orsatti, Uwe Koch, Raffaele De Francesco, David B. Olsen, Steven S. Carroll*, Giovanni Migliaccio

*Corresponding author for this work

Research output: Contribution to journalArticle

122 Scopus citations

Abstract

The RNA-dependent RNA polymerase of hepatitis C virus (HCV) is necessary for the replication of viral RNA and thus represents an attractive target for drug development. Several structural classes of nonnucleoside inhibitors (NNIs) of HCV RNA polymerase have been described, including a promising series of benzothiadiazine compounds that efficiently block replication of HCV subgenomic replicons in tissue culture. In this work we report the selection of replicons resistant to inhibition by the benzothiadiazine class of NNIs. Four different single mutations were identified in separate clones, and all four map to the RNA polymerase gene, validating the polymerase as the antiviral target of inhibition. The mutations (M414T, C451R, G558R, and H95R) render the HCV replicons resistant to inhibition by benzothiadiazines, though the mutant replicons remain sensitive to inhibition by other nucleoside and NNIs of the HCV RNA polymerase. Additionally, cross-resistance studies and synergistic inhibition of the enzyme by combinations of a benzimidazole and a benzothiadiazine indicate the existence of nonoverlapping binding sites for these two structural classes of inhibitors.

Original languageEnglish (US)
Pages (from-to)938-946
Number of pages9
JournalJournal of virology
Volume78
Issue number2
DOIs
StatePublished - Jan 1 2004

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Tomei, L., Altamura, S., Bartholomew, L., Bisbocci, M., Bailey, C., Bosserman, M., Cellucci, A., Forte, E., Incitti, I., Orsatti, L., Koch, U., De Francesco, R., Olsen, D. B., Carroll, S. S., & Migliaccio, G. (2004). Characterization of the Inhibition of Hepatitis C Virus RNA Replication by Nonnucleosides. Journal of virology, 78(2), 938-946. https://doi.org/10.1128/JVI.78.2.938-946.2004