Development of Hepatitis C Virus Inhibitors

丙型肝炎病毒抑制剂的开发

• 批准号: 6936833
• 负责人: Glen Andrew Coburn
• 金额: $ 99.69万
• 依托单位: PROGENICS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6936833
• 关键词: antiviral agents; bioassay; cell line; drug discovery /isolation; drug screening /evaluation; hepatitis C; hepatitis C virus; high throughput technology; liver cells; technology /technique development; virus envelope; virus infection mechanism

DESCRIPTION (provided by applicant): The development of new therapeutic agents for Hepatitis C virus (HCV) infection is a major public health priority. It is estimated that 170 million people worldwide, including approximately 4 million individuals in the United States, are infected with HCV. Available therapies are non-specific antiviral agents with modest efficacies and significant toxicities. We have selected HCV entry as a target for the discovery and development of novel antiviral agents. This stage of the virus life cycle represents an important target for drug development, and we have had success in the discovery and development of entry inhibitors for HIV that have now progressed to human clinical trials. In the Phase project, we generated novel HCV structural glycoprotein constructs that were used for the production of HCV pseudoparticles (HCVpp). We demonstrated that the HCVpp were able to specifically infect human liver cells, and that entry was sensitive to specific inhibitors. The HCV entry assay recapitulates the essential biology of this stage of the viral life cycle and may have potential utility for identifying new antiviral compounds. The overall goal of this Phase II project is to (1) adapt the entry assay to a high throughput screen (HTS) in 384-well format; (2) screen libraries of 100,000 diverse, drug-like compounds; (3) test active hits for breadth and potency of activity against genotypically diverse HCV isolates as well as a panel of unrelated viruses; and (4) determine the mechanism of action and molecular targets of inhibition in a panel of novel follow-on assays. Success in the Phase project is defined as the identification of 1 or more bona fide lead series of drug-like compounds that warrant optimization for potency, specificity and oral activity.

描述（由申请人提供）：开发丙型肝炎病毒（HCV）感染的新治疗剂是一项重要的公共卫生优先事项。据估计，全世界有 1.7 亿人感染 HCV，其中美国约有 400 万人。可用的疗法是非特异性抗病毒药物，其疗效有限且毒性显着。我们选择HCV进入作为发现和开发新型抗病毒药物的目标。病毒生命周期的这一阶段代表了药物开发的重要目标，我们在发现和开发艾滋病毒进入抑制剂方面取得了成功，现已进入人体临床试验。在 Phase 项目中，我们生成了新型 HCV 结构糖蛋白构建体，用于生产 HCV 假颗粒 (HCVpp)。我们证明 HCVpp 能够特异性感染人类肝细胞，并且该进入对特定抑制剂敏感。 HCV 进入测定概括了病毒生命周期这一阶段的基本生物学，并且可能具有识别新抗病毒化合物的潜在用途。该 II 期项目的总体目标是 (1) 使入门检测适应 384 孔格式的高通量筛选 (HTS)； (2) 筛选 100,000 种不同的药物样化合物库； (3) 测试活性命中针对基因型不同的 HCV 分离株以及一组不相关病毒的活性广度和效力； (4) 在一组新颖的后续测定中确定作用机制和抑制的分子靶点。该阶段项目的成功被定义为鉴定出一种或多种真正的先导系列药物化合物，这些化合物需要优化效力、特异性和口服活性。