2'-AND/OR 4'-C-MODIFIED NUCLEOSIDES AS ANTI-HCV AGENTS

描述（由申请人提供）：由于反应率低、毒副作用和不能持续的病毒载量降低，目前治疗慢性HCV感染的方法是不充分的。与其他慢性感染（HBV和HIV-1）一样，很可能需要多种药物的长期治疗才能成功治疗慢性HCV感染，并显著减少或消除进行性肝细胞损伤和肝细胞癌。唯一获得许可的慢性HCV治疗方法是干扰素(IFN)- α，可以单独使用，也可以与利巴韦林联合使用。目前，利巴韦林和干扰素- α联合治疗6至12个月是HCV感染的首选治疗方法。治疗的总体持续缓解率为40%，定义为治疗完成后6个月血清中HCV的消失。因此，迫切需要更好的药物来治疗慢性HCV感染。我们设计了一种利用HCV复制子系统的新型HCV抗病毒筛选技术。使用这种方法，我们鉴定了具有有效和选择性体外抗hcv活性的修饰核苷类似物。在这项拨款申请中，我们计划设计和合成总共190种新的2'- c -和/或4'- c -修饰核苷，以及3'-脱氧核苷作为潜在的抗hcv药物。我们将在体外测定一系列新设计的化合物的抗hcv活性。此外，为了准备体内原理证明研究，候选化合物的足够安全性和良好的药代动力学（PK）谱将在相关动物模型中确定。此外，有效的HCV聚合酶抑制剂将用于筛选耐药病毒突变体，因此，选择具有适当突变的HCV复制子将是本建议的相关部分。

DESCRIPTION (provided by applicant): Current therapies for chronic HCV infections are inadequate because of low response rates, toxic side effects, and unsustained viral load reductions. As with other chronic infections (HBV and HIV-1), long-term therapy with multiple drugs will most likely be required to successfully treat chronic HCV infections and significantly reduce or eliminate progressive hepatocellular damage and hepatocellular carcinoma. The only licensed therapy for chronic HCV is interferon (IFN)-alpha, either alone or in combination with ribavirin. Combination therapy with ribavirin and IFN-alpha for 6 to 12 months is currently the treatment of choice for HCV infection. The overall sustained response rate to treatment, defined as loss of HCV from serum 6 months after completion of treatment, is 40%. Thus, there is an urgent need for better agents to treat chronic HCV infections. We have designed a novel antiviral against HCV screening technology using the HCV replicon system. Using this approach we identified modified nucleoside analogues with potent and selective in vitro anti-HCV activity. In this grant proposal, we plan to design and synthesize a total of one hundred and ninety novel 2'-C- and/or 4'-C-modified nucleosides, as well as 3'-deoxynucleosides as potential anti-HCV agents. We will determine the anti-HCV activity of a series of newly designed compounds in vitro. In addition, in preparation for in vivo proof of principle studies, adequate safety and favorable pharmacokinetic (PK) profiles of candidate compounds will be determined in relevant animal models. Furthermore, potent HCV polymerase inhibitors will be used to select for drug-resistant viral mutants, and therefore, selection of HCV replicons with the proper mutations will be a relevant part of this proposal.