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

2-和/或4-C-修饰核苷作为抗HCV剂

• 批准号: 6947943
• 负责人: JINFA DU
• 金额: $ 19.5万
• 依托单位: PHARMASSET, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6947943
• 关键词: Macaca fascicularis; SDS polyacrylamide gel electrophoresis; antiviral agents; biotherapeutic agent; chemical synthesis; dosage; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; hepatitis C; hepatitis C virus; laboratory mouse; nucleoside analog; pharmacokinetics; polymerase chain reaction; replicon; site directed mutagenesis; tissue /cell culture; western blottings

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.

描述（由申请人提供）：由于反应率低，有毒副作用和不持续的病毒负荷减少，慢性HCV感染的当前疗法不足。与其他慢性感染（HBV和HIV-1）一样，很可能需要使用多种药物的长期治疗才能成功治疗慢性HCV感染，并显着降低或消除进行性肝细胞损伤和肝细胞癌。慢性HCV的唯一许可疗法是干扰素（IFN）-Alpha，无论是单独还是与利巴韦林结合使用。目前，与利巴韦林和IFN-Alpha结合治疗6至12个月是HCV感染的首选治疗方法。治疗的总体持续反应率定义为治疗后6个月血清中HCV的损失为40％。因此，迫切需要更好的药物来治疗慢性HCV感染。我们使用HCV复制子系统设计了针对HCV筛查技术的新型抗病毒。使用这种方法，我们确定了具有有效和选择性的体外抗HCV活性的修饰核苷类似物。在这项赠款建议中，我们计划设计和合成一百九十个新型2'-C-和/或4'-C修饰的核苷，以及3'-脱氧核苷作为潜在的抗HCV剂。我们将在体外确定一系列新设计的化合物的抗HCV活性。此外，为了准备原理研究的体内证明，将在相关动物模型中确定候选化合物的足够安全性和有利的药代动力学（PK）剖面。此外，有效的HCV聚合酶抑制剂将用于选择耐药病毒突变体，因此，选择具有适当突变的HCV复制子将是该建议的相关部分。