HEPATITIS C VIRUS NS5B POLYMERASE INHIBITORS

丙型肝炎病毒 NS5B 聚合酶抑制剂

• 批准号: 2792875
• 负责人: CURT H. HAGEDORN
• 金额: $ 9.96万
• 依托单位: TRIANGLE PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2792875
• 关键词: Escherichia coli; RNA directed DNA polymerase; antiviral agents; cell line; drug design /synthesis /production; drug screening /evaluation; enzyme activity; enzyme inhibitors; hepatitis C virus; nucleotidyltransferase; transfection

Chronic hepatitis C is a major unsolved public health problem that afflicts 4 million people and results in 10,000 deaths per year in the USA. Although more than 50 percent of patients eventually succumb to liver failure and/or hepatocellular carcinoma, this frequently takes 20-30 years to develop. This provides a large window for the treatment and prevention of the long-term sequelae of this chronic infection. Unfortunately, current treatments for chronic HCV remain relatively ineffective and frequently have side effects. The hepatitis C virus NS5B polymerase (or RDRP) has been an understudied target for the development of new hepatitis C therapeutics. The primary goal of this work is to further characterize a novel cell-based HCV NS5B polymerase system and use it to identify small molecule inhibitors of NS5B polymerase that may lead to new hepatitis C therapeutics. Hypothesis: This novel mammalian cell-based system will provide the means for identifying and studying small molecules that selectively inhibit the HCV NS5B polymerase and can provide new treatment options for chronic hepatitis C. Specific Objectives: To identify small molecules that inhibit NS5B polymerase, particularly those requiring metabolic activation, using a mammalian cell-based system. To further develop the mammalian cell-based assay so that it has the ability to identify an even broader category of NS5B polymerase inhibitors within mammalian cells. Determine the specificity and toxicity of inhibitors of NS5B polymerase using in vitro assays of mammalian DNA and RNA polymerases, and mammalian cell toxicity assays. PROPOSED COMMERCIAL APPLICATION The market for an effective therapy for chronic hepatitis C is enormous. Approximately 4 million people in the USA have chronic hepatitis C and the world-wide incidence of chronic HCV is estimated at 1.5-2.5 percent. A patent on the mammalian cell NS5B-template/reporter system has been filed by Emory University School of Medicine and licensed to Triangle Pharmaceuticals.

慢性丙型肝炎是一个主要的未解决的公共卫生问题，在美国每年折磨400万人并导致10，000人死亡。 虽然超过50%的患者最终死于肝衰竭和/或肝细胞癌，但这通常需要20-30年的时间才能发展。 这为治疗和预防这种慢性感染的长期后遗症提供了一个很大的窗口。 不幸的是，目前对慢性HCV的治疗仍然相对无效，并且经常有副作用。 丙型肝炎病毒NS 5 B聚合酶（或RDRP）一直是开发新的丙型肝炎治疗药物的研究目标。 这项工作的主要目标是进一步表征一种新的基于细胞的HCV NS 5 B聚合酶系统，并使用它来鉴定NS 5 B聚合酶的小分子抑制剂，这可能导致新的丙型肝炎治疗方法。假设：这种新的哺乳动物细胞为基础的系统将提供用于识别和研究选择性抑制HCV NS 5 B聚合酶的小分子的手段，并可以为慢性丙型肝炎提供新的治疗选择。具体目标：使用基于哺乳动物细胞的系统鉴定抑制NS 5 B聚合酶的小分子，特别是需要代谢活化的小分子。 进一步开发基于哺乳动物细胞的检测方法，使其能够鉴定哺乳动物细胞内更广泛类别的NS 5 B聚合酶抑制剂。 使用哺乳动物DNA和RNA聚合酶的体外试验以及哺乳动物细胞毒性试验确定NS 5 B聚合酶抑制剂的特异性和毒性。建议的商业应用慢性丙型肝炎有效治疗的市场是巨大的。 美国约有400万人患有慢性丙型肝炎，全球慢性HCV的发病率估计为1.5- 2.5%。 哺乳动物细胞NS 5 B模板/报告系统的专利已由埃默里大学医学院提交，并授权给三角制药公司。