Bristol Myer Squibb Company, Wallingford, CT 06492, United States.
Curr Opin Virol. 2013 Oct;3(5):514-20. doi: 10.1016/j.coviro.2013.06.014. Epub 2013 Jul 27.
Treatment of Hepatitis C Virus (HCV) infection is rapidly evolving with the introduction of direct acting antiviral agents (DAA). HCV NS5A replication complex inhibitors, exemplified by Daclatasvir (BMS-790052), represent a new class of DAA. The exceptional in vitro potency (EC50 values at pM to low nM range) and broad genotype coverage of NS5A inhibitors have translated to robust anti-HCV effects in infected patients, making NS5A inhibitors an essential component of effective HCV DAA combination therapies. On the basis of drug-induced resistance substitutions and computer modeling, NS5A inhibitors most likely act at the N-terminus of NS5A (domain I). Mechanism of inhibition studies to elucidate the exquisite potency of these inhibitors have generated several working models.
治疗丙型肝炎病毒 (HCV) 感染正在迅速发展，直接作用抗病毒药物 (DAA) 的引入是一个重要的进展。HCV NS5A 复制复合物抑制剂，如达卡他韦 (BMS-790052)，代表了一类新的 DAA。NS5A 抑制剂具有出色的体外效力 (EC50 值在皮摩尔至低纳摩尔范围内) 和广泛的基因型覆盖范围，这使得 NS5A 抑制剂在感染患者中具有强大的抗 HCV 作用，使 NS5A 抑制剂成为有效 HCV DAA 联合治疗的重要组成部分。基于药物诱导的耐药性替换和计算机建模，NS5A 抑制剂很可能作用于 NS5A 的 N 端 (结构域 I)。为阐明这些抑制剂的高活性而进行的抑制机制研究产生了几种工作模型。
