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.

简介(申请人提供)：盖尔曼博士是一名医学博士/博士，曾接受过有机化学和传染病方面的培训，他的近期职业目标是分子病毒学和相关学科的高级培训，他的长期职业目标是学术医学职位。他建议使用一类新的小分子--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杰弗里·格伦博士的实验室进行，与共同导师凯文·肖卡特博士(加州大学旧金山分校细胞和分子药理学)、顾问加里·佩尔茨博士(麻醉学；药代动力学和药物代谢方面的专业知识)和迈克尔·林博士(儿科学/生物工程；活细胞生物分子成像专业知识)一起进行。斯坦福大学有一个充满活力的传染病部门，并为准备过渡到教师职位的博士后研究员提供广泛的职业支持。丙型肝炎病毒(丙型肝炎病毒)感染了全球人口的2%-3%，约1.7亿人。慢性丙型肝炎病毒感染带来25%的肝硬变风险和较小但严重的威胁生命的肝细胞癌风险。在美国，丙型肝炎病毒引起的肝硬变是肝移植的主要适应症，但丙型肝炎病毒总是会在移植的器官中复发。目前丙型肝炎病毒治疗的标准是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，这是昂贵的，有多种严重的副作用，只有50%-80%有效。尽管多种新的抗丙型肝炎病毒疗法正处于不同的发展阶段，但为了有效地控制感染，多药联合疗法可能是必要的。丙型肝炎病毒非结构蛋白NS5A与膜磷脂酰肌醇PI(4，5)P2或PIP2特异性结合。这种相互作用和产生PIP2的磷脂酰肌醇4-激酶(PI4K)活性似乎都是病毒复制所必需的。这项拟议的研究包括表征旨在抑制PI4K的化合物的潜力：(1)一类新型的抗丙型肝炎病毒药物，其机制与已知的抗病毒药物无关；(2)一种化学工具，用于研究丙型肝炎病毒的生命周期，特别是丙型肝炎病毒复制酶复合体的动力学，使用荧光蛋白标记显示活细胞中的复制酶复合体。与抑制病毒酶相比，抑制宿主酶PI4K可能与更高的抗药性发展障碍有关。丙型肝炎病毒(HCV)每年会导致肝癌、肝功能衰竭和数千人死亡，它依赖于它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，以确定它们是否可能导致一种新的抗丙型肝炎病毒药物。我们还将使用这些化合物来研究丙型肝炎病毒如何复制自己，以及这一过程如何依赖于PI4K的活性。