Pharmasset, Inc., Princeton, NJ 08540, USA.
Future Med Chem. 2009 Nov;1(8):1429-52. doi: 10.4155/fmc.09.88.
Chronic hepatitis C virus (HCV) infection is a global health problem, with over 170 million people infected worldwide. The current therapy, pegylated interferon (PEG-IFN) plus ribavirin (RBV), provides only approximately a 40% sustained virological response (undetectable HCV RNA for greater than 24 weeks after cessation of therapy), in genotype 1-infected individuals. In addition to the limited sustained virological response, PEG-IFN/RBV treatment is associated with serious adverse effects. Nucleosides have long been the cornerstone of antiviral therapy because of their proven efficacy and high barrier to resistance. Through the use of surrogate viruses or the HCV subgenomic replicon, several classes of nucleoside analogs or their monophosphate prodrugs have been identified that inhibit HCV RNA replication. Nucleoside analogs that possess the 2´-C-methyl modification vary in their ability to be phosphorylated and to act as alternative substrate inhibitors of the HCV RNA polymerase. Herein, we discuss various classes of nucleoside inhibitors, with a focus on available structure-activity relationships, their mode of action and resistance profile.
慢性丙型肝炎病毒 (HCV) 感染是一个全球性的健康问题，全世界有超过 1.7 亿人感染。目前的治疗方法是聚乙二醇干扰素 (PEG-IFN) 加利巴韦林 (RBV)，在感染 1 型 HCV 的个体中，其持续病毒学应答率（治疗停止后 24 周以上 HCV RNA 不可检测）仅约为 40%。除了持续病毒学应答有限外，PEG-IFN/RBV 治疗还会引起严重的不良反应。核苷类药物长期以来一直是抗病毒治疗的基石，因为它们具有已证实的疗效和高耐药屏障。通过使用替代病毒或 HCV 亚基因组复制子，已经确定了几类核苷类似物或其单磷酸前药，它们可以抑制 HCV RNA 复制。具有 2´-C-甲基修饰的核苷类似物在磷酸化能力和作为 HCV RNA 聚合酶的替代底物抑制剂方面存在差异。本文将重点讨论各种类型的核苷抑制剂，包括其现有的结构-活性关系、作用机制和耐药谱。
