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In vitro selected Con1 subgenomic replicons resistant to 2′-C-Methyl-Cytidine or to R1479 show lack of cross resistance
- Source :
-
Virology . Aug2006, Vol. 351 Issue 2, p349-359. 11p. - Publication Year :
- 2006
-
Abstract
- Abstract: The HCV polymerase is an attractive target for the development of new and specific anti-HCV drugs. Herein, the characterization of the inhibitory effect of 2′-C-Methyl-Cytidine shows that it is a potent inhibitor of both genotype 1b and 1a HCV replicon replication, both of laboratory-optimized as well as of NS5B clinical isolates–chimera replicons. The corresponding 5′-triphosphate derivative is a potent inhibitor of native HCV replicase isolated from replicon cells and of the recombinant genotype 1b and 1a HCV polymerase-mediated RNA synthesis. Resistance to 2′-C-Methyl-Cytidine was mapped to amino acid substitution S282T in the NS5B coding region. Cross-resistance was observed to 2′-C-Methyl-Adenosine but not to interferon α-2a, to non-nucleoside HCV polymerase inhibitors or to R1479, a new and potent nucleoside inhibitor of NS5B polymerase. In vitro studies mapped resistance to R1479 to amino acid substitutions S96T and S96T/N142T of the NS5B polymerase. These mutations did not confer resistance to 2-C-Methyl-Cytidine, thus confirming the lack of cross-resistance between these two HCV inhibitors. These data will allow the optimization of new polymerase inhibitors and their use in combination therapy. [Copyright &y& Elsevier]
- Subjects :
- *HEPATITIS C virus
*HEPATITIS C
*LIVER diseases
*DRUG resistance
Subjects
Details
- Language :
- English
- ISSN :
- 00426822
- Volume :
- 351
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- Virology
- Publication Type :
- Academic Journal
- Accession number :
- 21775496
- Full Text :
- https://doi.org/10.1016/j.virol.2006.03.045