Antivirals for Hepatitis C Targeting Phosphoinositide Metabolism

针对磷酸肌醇代谢的丙型肝炎抗病毒药物

• 批准号: 8822800
• 负责人: Michael A Gelman
• 金额: $ 13.32万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-11-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8822800
• 关键词: 1-Phosphatidylinositol 3-Kinase; 1-Phosphatidylinositol 4-Kinase; Address; Adverse effects; Affect; Anesthesia procedures; Animal Model; Antiviral Agents; Antiviral resistance; Basic Amino Acids; Binding; Biological; Biological Models; Biomedical Engineering; Cell Culture Techniques; Cell membrane; Cells; Cessation of life; Chemicals; Chronic Hepatitis C; Cirrhosis; Clinical; Collaborations; Combined Modality Therapy; Communicable Diseases; Complement; Complex; Development; Discipline; Doctor of Philosophy; Drug Kinetics; Drug resistance; Enzymes; Faculty; Frequencies; Genotype; Goals; Half-Life; Hepatitis C; Hepatitis C Antiviral; Hepatitis C virus; Human; Image; Individual; Infection Control; Internet; Kinetics; Laboratories; Lead; Life; Life Cycle Stages; Liver; Liver Failure; Maintenance; Malignant neoplasm of liver; Medicine; Membrane; Membrane Lipids; Mentors; Metabolism; Molecular; Molecular Virology; Mutate; Mutation; Nonstructural Protein; Organ Transplantation; Organic Chemistry; Pattern; Pediatrics; Pharmaceutical Preparations; Pharmacology; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phosphotransferases; Plasmodium falciparum; Play; Population; Positioning Attribute; Postdoctoral Fellow; Primary carcinoma of the liver cells; Process; Production; Protease Inhibitor; Proteins; RNA Viruses; Regimen; Replicon; Research; Resistance; Resistance development; Rhinovirus; Ribavirin; Risk; Role; Small Interfering RNA; Staging; Structure; System; Testing; Therapeutic; Toxic effect; Training; Universities; Viral; Viral Genes; Virus Inhibitors; Virus Replication; Work; analog; anti-hepatitis C; career; design; drug metabolism; improved; in vivo; inorganic phosphate; kinase inhibitor; liver transplantation; mouse model; mutant; novel; pathogen; phosphatidylinositol 4-phosphate; replicase; resistance mutation; response; small molecule; standard of care; tool; viral resistance

DESCRIPTION (provided by applicant): Dr. Gelman, an MD/PhD with prior training in organic chemistry and infectious diseases, whose immediate career goal is advanced training in molecular virology and related disciplines and whose long-term career goal is a position in academic medicine, proposes to study the hepatitis C virus using a novel class of small molecules, the PI4K inhibitors. The proposed work will take place at Stanford University, in Dr. Jeffrey Glenn's laboratory, with co-mentor Dr. Kevan Shokat (UCSF Cellular and Molecular Pharmacology) and consultants Dr. Gary Peltz (Anesthesia; expertise in pharmacokinetics and drug metabolism) and Dr. Michael Lin (Pediatrics/Bioengineering; expertise in imaging biological molecules in living cells). Stanford has a vibrant Infectious Diseases division and extensive career support for postdoctoral fellows as they prepare to make the transition to faculty positions. The hepatitis C virus (HCV) infects between 2-3% of the global population, or roughly 170 million people. Chronic HCV infection carries a 25% risk of cirrhosis and a smaller but significant risk of life-threatening hepatocellular cancer. Cirrhosis due to HCV is the leading indication for liver transplant in the US, but HCV invariably recurs in the transplanted organ. The current standard of care for HCV treatment is a 12-48 week (depending on genotype and response) course of peginterferon-ribavirin, which is costly, has multiple serious side effects, and is only 50-80% effective. Although multiple new classes of anti-HCV therapies are in various stages of development, multidrug combination therapy is likely to be necessary for effective control of the infection. The HCV nonstructural protein NS5A interacts specifically with membrane phosphoinositide PI(4,5)P2, or PIP2. Both this interaction and the phosphoinositide 4-kinase (PI4K) activity that generates PIP2 appear to be necessary for viral replication. The proposed research involves characterization of the potential of compounds designed to inhibit PI4K as (1) a novel class of antivirals for HCV with a mechanism unrelated to known antiviral drugs and (2) a chemical tool to investigate the HCV life cycle, and particularly the dynamics of the HCV replicase complex, using fluorescent protein tags to visualize replicase complexes in living cells. Inhibition of PI4K, which is a host enzyme, may be associated with higher barriers to development of resistance than is inhibition of viral enzymes. The hepatitis C virus (HCV), which causes liver cancer, liver failure, and thousands of deaths per year, depends on an enzyme called PI4K in the cells it infects. We will investigate a class of chemical compounds that can block PI4K to determine whether they could lead to a new class of drugs against HCV. We will also use these compounds to investigate how HCV makes copies of itself and how this process depends on the activity of PI4K.

描述（由申请人提供）：Gelman 博士，医学博士/博士，接受过有机化学和传染病方面的培训，其近期职业目标是分子病毒学和相关学科的高级培训，其长期职业目标是在学术领域担任职位医学，建议使用一类新型小分子 PI4K 抑制剂来研究丙型肝炎病毒。拟议的工作将在斯坦福大学 Jeffrey Glenn 博士的实验室进行，共同导师 Kevan Shokat 博士（加州大学旧金山分校细胞和分子药理学）和顾问 Gary Peltz 博士（麻醉；药代动力学和药物代谢方面的专业知识）和 Dr. Michael Lin（儿科/生物工程；活细胞中生物分子成像方面的专业知识）。斯坦福大学拥有一个充满活力的传染病部门，并为准备过渡到教职的博士后提供广泛的职业支持。丙型肝炎病毒 (HCV) 感染全球 2-3% 的人口，即大约 1.7 亿人。慢性 HCV 感染有 25% 的肝硬化风险，以及较小但显着的危及生命的肝细胞癌风险。 HCV 引起的肝硬化是美国肝移植的主要适应症，但 HCV 总是在移植器官中复发。目前 HCV 治疗的护理标准是 12-48 周（取决于基因型和反应）的聚乙二醇干扰素-利巴韦林疗程，成本昂贵，具有多种严重副作用，并且有效率仅为 50-80%。尽管多种新型抗 HCV 疗法正处于不同的开发阶段，但多药联合疗法可能是有效控制感染所必需的。 HCV 非结构蛋白 NS5A 与膜磷酸肌醇 PI(4,5)P2 或 PIP2 特异性相互作用。这种相互作用和产生 PIP2 的磷酸肌醇 4 激酶 (PI4K) 活性似乎都是病毒复制所必需的。拟议的研究涉及旨在抑制 PI4K 的化合物作为（1）一类新型 HCV 抗病毒药物的潜力，其机制与已知抗病毒药物无关；（2）研究 HCV 生命周期的化学工具，特别是HCV 复制酶复合物的动力学，使用荧光蛋白标签可视化活细胞中的复制酶复合物。与抑制病毒酶相比，抑制宿主酶 PI4K 可能与更高的耐药性发展障碍相关。丙型肝炎病毒 (HCV) 每年导致肝癌、肝功能衰竭和数千人死亡，其依赖于其感染的细胞中一种名为 PI4K 的酶。我们将研究一类可以阻断 PI4K 的化合物，以确定它们是否可以产生一类新的抗 HCV 药物。我们还将使用这些化合物来研究 HCV 如何复制自身以及该过程如何依赖于 PI4K 的活性。