Tibotec-Virco Virology BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium.
Antimicrob Agents Chemother. 2011 Aug;55(8):3812-20. doi: 10.1128/AAC.00214-11. Epub 2011 May 16.
Chronic infection with hepatitis C virus (HCV) is a major global health burden and is associated with an increased risk of liver cirrhosis and hepatocellular carcinoma. Current therapy for HCV infection has limited efficacy, particularly against genotype 1 virus, and is hampered by a range of adverse effects. Therefore, there is a clear unmet medical need for efficacious and safe direct antiviral drugs for use in combination with current treatments to increase cure rates and shorten treatment times. The broad genotypic coverage achievable with nucleosides or nucleotides and the high genetic barrier to resistance of these compounds observed in vitro and in vivo suggest that this class of inhibitors could be a valuable component of future therapeutic regimens. Here, we report the in vitro inhibitory activity and mode of action of 2'-deoxy-2'-spirocyclopropylcytidine (TMC647078), a novel and potent nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase that causes chain termination of the nascent HCV RNA chain. In vitro combination studies with a protease inhibitor resulted in additive efficacy in the suppression of HCV RNA replication, highlighting the potential for the combination of these two classes in the treatment of chronic HCV infection. No cytotoxic effects were observed in various cell lines. Biochemical studies indicated that TMC647078 is phosphorylated mainly by deoxycytidine kinase (dCK) without inhibiting the phosphorylation of the natural substrate, and high levels of triphosphate were observed in Huh7 cells and in primary hepatocytes in vitro. TMC647078 is a potent novel nucleoside inhibitor of HCV replication with a promising in vitro virology and biology profile.
慢性丙型肝炎病毒 (HCV) 感染是一个全球性的重大健康负担，与肝硬化和肝细胞癌的风险增加有关。目前 HCV 感染的治疗方法疗效有限，特别是针对基因型 1 病毒，并且受到一系列不良反应的限制。因此，迫切需要有效的、安全的直接抗病毒药物与现有治疗方法联合使用，以提高治愈率并缩短治疗时间。核苷或核苷酸具有广泛的基因型覆盖范围，并且这些化合物在体外和体内观察到的高遗传耐药性，表明这类抑制剂可能成为未来治疗方案的有价值组成部分。在这里，我们报告了 2'-脱氧-2'-螺环丙基胞苷（TMC647078）的体外抑制活性和作用机制，TMC647078 是一种新型、有效的 HCV NS5B RNA 依赖性 RNA 聚合酶的核苷抑制剂，导致新生 HCV RNA 链的链终止。与蛋白酶抑制剂的体外联合研究表明，抑制 HCV RNA 复制的效果具有加性，突出了这两类药物联合治疗慢性 HCV 感染的潜力。在各种细胞系中未观察到细胞毒性作用。生化研究表明，TMC647078 主要由脱氧胞苷激酶 (dCK) 磷酸化，而不抑制天然底物的磷酸化，并且在 Huh7 细胞和原代肝细胞中观察到高水平的三磷酸。TMC647078 是一种新型有效的 HCV 复制核苷抑制剂，具有有前途的体外病毒学和生物学特性。
