Characterization of the inhibition of hepatitis C virus RNA replication by nonnucleosides.
J Virol
; 78(2): 938-46, 2004 Jan.
Article
en En
| MEDLINE
| ID: mdl-14694125
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Antivirales
/
Replicación Viral
/
Bencimidazoles
/
Benzotiadiazinas
/
ARN Polimerasa Dependiente del ARN
/
Hepacivirus
Límite:
Humans
Idioma:
En
Revista:
J Virol
Año:
2004
Tipo del documento:
Article
País de afiliación:
Italia