Sofia Michael J
Pharmasset, Inc., Princeton, NJ, USA.
Antivir Chem Chemother. 2011 Aug 23;22(1):23-49. doi: 10.3851/IMP1797.
HCV infection is a significant worldwide health problem and is a major cause of hepatocellular carcinoma. The current standard of care, interferon and ribavirin, is only effective against a proportion of the patient population infected with HCV. To address the shortcomings of existing therapy, the development of direct acting antiviral agents is under investigation. The HCV RNA dependent RNA polymerase is an essential enzyme for viral replication and is therefore a logical target against which to develop novel anti-HCV agents. Nucleosides have been shown to be effective as antiviral agents for other viral diseases and therefore, have been investigated as inhibitors of HCV replication. The development of prodrugs of nucleoside 5'-monophosphates has been pursued to address limitations associated with poor nucleoside phosphorylation. This is required to produce the nucleoside 5'-triphosphate which is the anabolite that is the actual inhibitor of the polymerase enzyme. Prodrugs of nucleoside 5'-monophosphates have been developed that enable their delivery into cells and in vivo into the liver. The implementation of these prodrug strategies has ultimately led to the identification of several prodrugs of nucleoside 5'-monophosphates that are potent inhibitors of HCV replication in vitro. They have progressed into the clinic and the early data demonstrate greatly reduced viral load levels in HCV-infected patients. This review will survey the state of nucleotide prodrugs for the treatment of HCV.
丙型肝炎病毒（HCV）感染是一个全球性的重大健康问题，也是肝细胞癌的主要病因。目前的标准治疗方法，即干扰素和利巴韦林，仅对一部分感染HCV的患者有效。为解决现有疗法的不足，直接作用抗病毒药物的研发正在进行中。HCV RNA依赖性RNA聚合酶是病毒复制所必需的酶，因此是开发新型抗HCV药物的合理靶点。核苷已被证明对其他病毒性疾病有效，因此已被研究作为HCV复制的抑制剂。为解决与核苷磷酸化不良相关的局限性，人们一直在研发核苷5'-单磷酸的前药。这是产生核苷5'-三磷酸所必需的，核苷5'-三磷酸是合成代谢产物，是聚合酶的实际抑制剂。已开发出核苷5'-单磷酸的前药，使其能够进入细胞并在体内进入肝脏。这些前药策略的实施最终导致鉴定出几种核苷5'-单磷酸的前药，它们在体外是HCV复制的有效抑制剂。它们已进入临床试验，早期数据表明HCV感染患者的病毒载量水平大幅降低。本综述将概述用于治疗HCV的核苷酸前药的现状。
