Le Pogam Sophie, Jiang Wen-Rong, Leveque Vincent, Rajyaguru Sonal, Ma Han, Kang Hyunsoon, Jiang Sharon, Singer Margaret, Ali Samir, Klumpp Klaus, Smith Dave, Symons Julian, Cammack Nick, Nájera Isabel
Roche Palo Alto LLC, S3-1, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
Virology. 2006 Aug 1;351(2):349-59. doi: 10.1016/j.virol.2006.03.045. Epub 2006 May 19.
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 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.
丙型肝炎病毒（HCV）聚合酶是开发新型特异性抗HCV药物的一个有吸引力的靶点。在此，对2'-C-甲基胞苷抑制作用的表征表明，它是1b型和1a型HCV复制子复制的有效抑制剂，无论是实验室优化的还是NS5B临床分离株-嵌合复制子。相应的5'-三磷酸衍生物是从复制子细胞中分离出的天然HCV复制酶以及重组1b型和1a型HCV聚合酶介导的RNA合成的有效抑制剂。对2'-C-甲基胞苷的耐药性定位到NS5B编码区的氨基酸取代S282T。观察到对2'-C-甲基腺苷有交叉耐药性，但对干扰素α-2a、非核苷类HCV聚合酶抑制剂或R1479（一种新型强效NS5B聚合酶核苷抑制剂）没有交叉耐药性。体外研究将对R1479的耐药性定位到NS5B聚合酶的氨基酸取代S96T和S96T/N142T。这些突变并未赋予对2'-C-甲基胞苷的耐药性，从而证实了这两种HCV抑制剂之间不存在交叉耐药性。这些数据将有助于新型聚合酶抑制剂的优化及其在联合治疗中的应用。
