Development of Hepatitis C Virus Inhibitors

描述（由申请人提供）：开发新的治疗丙型肝炎病毒（HCV）感染的药物是一个主要的公共卫生优先事项。据估计，全世界有1.7亿人感染丙型肝炎病毒，其中包括美国约400万人。可用的治疗方法是非特异性抗病毒药物，疗效适中，毒性显著。我们选择HCV作为发现和开发新型抗病毒药物的靶点。病毒生命周期的这一阶段是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，目前已进入人体临床试验阶段。在阶段项目中，我们生成了新的HCV结构糖蛋白构建物，用于生产HCV假颗粒（HCVpp）。我们证明了HCVpp能够特异性感染人类肝细胞，并且对特定抑制剂敏感。HCV进入试验概括了病毒生命周期这一阶段的基本生物学，可能在鉴定新的抗病毒化合物方面具有潜在的效用。第二阶段项目的总体目标是：(1)使进入分析适应384孔格式的高通量筛选（HTS）；(2)筛选10万种不同的类药物化合物的文库；(3)测试针对不同基因型HCV分离株以及一组不相关病毒的活性命中的广度和效力；(4)在一组新的后续检测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1个或多个真正的先导类药物化合物系列，并保证其效力、特异性和口服活性的优化。

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.