Mechanismof Action and Antiviral Activity of Benzimidazole-Based AllostericInhibitors of the Hepatitis C Virus RNA-Dependent RNAPolymerase

• DOI: 10.1128/jvi.77.24.13225-13231.2003
• Publication Date: 2003-11-25T22:59:20Z
• Authors: Licia Tomei; Sergio Altamura; Linda Bartholomew; Antonino Biroccio; Alessandra Ceccacci; Laura Pacini; Frank Narjes; Nadia Gennari; Monica Bisbocci; Ilario Incitti; Laura Orsatti; Steven Harper; Ian Stansfield; Michael Rowley; Raffaele De Franc...; Giovanni Migliaccio
• Keywords: NS5B; Benzimidazole

ABSTRACT The RNA-dependent RNA polymerase of hepatitis C virus (HCV) is the catalytic subunit viral amplification machinery and an appealing target for development new therapeutic agents against HCV infection. Nonnucleoside inhibitors based on a benzimidazole scaffold have been recently reported. Compounds this class are efficient replication in cell culture, thus providing attractive candidates further development. Here we report detailed analysis mechanism action selected inhibitors. Kinetic data binding experiments indicated that these compounds act as allosteric block activity prior to elongation step. Escape mutations confer resistance map proline 495, residue located surface thumb domain away from active site. Substitution sufficient make enzyme replicons resistant Interestingly, 495 lies identified noncatalytic GTP-binding site, validating it potential site can be targeted by small-molecule polymerase.