New antiviral therapies in the management of HCV infection

StephenW

New antiviral therapies in the management of HCV infection; Farnik H, Zeuzem S; Antiviral Therapy (May 2012)
Improved knowledge of the HCV life cycle and of structural features of HCV proteins have led to the discovery of numerous potential targets for antiviral therapy. Viral replication and polyprotein processing have been tagged as promising viral targets. Clathrin-mediated endocytosis, fusion of HCV with cellular membranes, translation of viral RNA, virus production and release as well as several host cell factors may provide alternative targets for future anti-HCV therapies. Several compounds are currently under investigation in clinical trials and showed high antiviral activity in patients with chronic hepatitis C. Recently, Phase III studies for two protease inhibitors, telaprevir and boceprevir, each given in combination with pegylated interferon (standard of care [SOC]), were completed. In HCV-genotype-1-infected patients, the addition of telaprevir or boceprevir to SOC increased sustained virological response rates from<50% to>70%. Nucleoside/nucleotide inhibitors of the HCV NS5B polymerase have shown antiviral activity against different HCV genotypes, and have a higher barrier to resistance than protease inhibitors. In addition, several allosteric binding sites have been identified for non-nucleoside inhibitors of the NS5B polymerase. Inhibitors of NS5A are potentially active against all HCV genotypes. Among the different host cell-targeting compounds, cyclophilin inhibitors have shown promising results. Future hope lies in the combination of direct-acting antiviral agents with the possibility of interferon-free treatment regimens.
改进知识的丙型肝炎病毒的生命周期和丙型肝炎病毒蛋白的结构特点，导致许多潜在的抗病毒治疗目标的发现。病毒复制和聚处理已标记为有前途的病毒目标。网格蛋白介导的内吞丙型肝炎病毒与细胞膜融合，病毒RNA的翻译，病毒的生产和发行以及几个宿主细胞因子可能为未来的抗-HCV治疗的替代目标。几种化合物目前正在调查在临床试验中，表现出较高的慢性丙型肝炎患者的抗病毒活性，三期两个蛋白酶抑制剂的研究，telaprevir治疗和boceprevir，每个组合给予聚乙二醇干扰素（护理[SOC的标准）已经完成。在丙型肝炎病毒基因型-1感染的病人，此外telaprevir治疗或boceprevir SOC的增加持续病毒学应答率<50％> 70％。核苷/核苷酸对丙型肝炎病毒NS5B聚合酶抑制剂对不同的丙型肝炎病毒基因型的抗病毒活性，并具有更高的比蛋白酶抑制剂耐药屏障。此外，一些变构结合位点已经确定非核苷NS5B聚合酶抑制剂。 NS5A的抑制剂有可能对丙型肝炎病毒基因型的活跃。不同的主机之间的细胞靶向化合物，亲环素抑制剂已显示出可喜的成果。未来的希望在于直接作用的抗病毒药物相结合的干扰素治疗方案的可能性。