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: 8636989
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636989
• 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/博士学位，并在有机化学和传染病方面进行了先前培训，其直接职业目标是分子病毒学和相关学科的高级培训，其长期职业目标是学术界的职位医学建议使用一类新型的小分子PI4K抑制剂研究丙型肝炎病毒。拟议的工作将在斯坦福大学，杰弗里·格伦（Jeffrey Glenn）的实验室，同事Kevan Shokat博士（UCSF Cellular and Molecular Pharmacology）和顾问Gary Peltz博士（麻醉；药代动力学和药物代谢性博士）以及DR DR DR DRED顾问Gary Peltz博士以及顾问迈克尔·林（Michael Lin）（儿科/生物工程；在活细胞中成像生物分子的专业知识）。斯坦福大学有充满活力的传染病部门，并为博士后研究员提供了广泛的职业支持，他们准备过渡到教职员工。丙型肝炎病毒（HCV）感染了全球人口2-3％，约1.7亿人。慢性HCV感染带有25％的肝硬化风险，并且危及生命的肝癌风险较小，但危及生命的危险风险较小。 HCV引起的肝硬化是美国肝移植的主要指示，但HCV总是在移植器官中恢复。 HCV治疗的当前护理标准是Peginterferon-ribavirin的12-48周（取决于基因型和反应），这是昂贵的，具有多种严重的副作用，仅有效50-80％。尽管多种新类别的抗HCV疗法处于发育的各个阶段，但多药结合疗法对于有效控制感染可能是必需的。 HCV非结构蛋白NS5A与膜磷酸肌醇PI（4,5）P2或PIP2特别相互作用。这种相互作用和产生PIP2的磷酸肌醇4-激酶（PI4K）活性似乎对于病毒复制都是必需的。拟议的研究涉及表征旨在抑制PI4K的化合物的潜力，因为（1）具有与已知抗病毒药的机制无关的HCV的新型抗病毒药物，以及（2）研究HCV生命周期的化学工具，尤其是化学工具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。抑制PI4K是一种宿主酶，可能与抑制病毒酶更高的耐药性障碍有关。肝炎病毒（HCV）每年引起肝癌，肝衰竭和数千例死亡，取决于IT感染细胞中称为PI4K的酶。我们将研究一类可以阻止PI4K的化合物，以确定它们是否可以导致针对HCV的新药物。我们还将使用这些化合物来研究HCV如何制作自身的副本，以及该过程如何取决于PI4K的活性。