In vitro selected Con1 subgenomic replicons resistant to 2′-C-methyl-cytidine or to R1479 show lack of cross resistance

被引：102

作者：

Le Pogam, Sophie ^{[1
]}

Jiang, Wen-Rong ^{[1
]}

Leveque, Vincent ^{[1
]}

Rajyaguru, Sonal ^{[1
]}

Ma, Han ^{[1
]}

Kang, Hyunsoon ^{[1
]}

Jiang, Sharon ^{[1
]}

Singer, Margaret ^{[1
]}

Ali, Samir ^{[1
]}

Klumpp, Klaus ^{[1
]}

Smith, Dave ^{[1
]}

Symons, Julian ^{[1
]}

Cammack, Nick ^{[1
]}

Najera, Isabel ^{[1
]}

机构：

[1] Roche Palo Alto LLC, Palo Alto, CA 94304 USA

来源：

VIROLOGY | 2006年 / 351卷 / 02期

关键词：

hepatitis C virus; treatment; NS5B polymerase; inhibitors; drug resistance; nucleoside analogs; combination therapy;

D O I：

10.1016/j.virol.2006.03.045

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

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 la 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 alpha-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. (c) 2006 Elsevier Inc. All rights reserved.

引用

页码：349 / 359

页数：11