Capsid-Targeting HIV-1 Antivirals

衣壳靶向 HIV-1 抗病毒药物

基本信息

批准号：
7931535
负责人：
Christopher R Aiken
金额：
$ 77.16万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-15 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7931535
关键词：
AIDS/HIV problem Affect Affinity Amino Acids Antiviral Agents Area Binding Biological Assay Biology Capsid Carcinoembryonic Antigen Peptide 1 Cells Cellular biology Chemicals Cherry - dietary Collaborations Complement Core Assembly Cyclophilin A Cyclosporine Data Dependence Development Disease Dissociation Drug Delivery Systems Drug resistance Goals HIV HIV Infections HIV-1 Image In Vitro Infection Inhibitory Concentration 50 Kinetics Label Lead Length Life Cycle Stages Molecular Molecular Target Monitor Mutation Mutation Spectra N-terminal Pharmaceutical Preparations Process Proteins Recombinants Research Research Project Grants Resistance Screening procedure Serial Passage Staging Structure Surface Testing Therapeutic Time Viral Viral Physiology Virion Virus Virus Assembly Virus Diseases X-Ray Crystallography base cell type crosslink design drug development effective therapy improved inhibitor/antagonist insight mutant novel particle premature prevent public health relevance research and development research study resistance mutation scaffold small molecule structural biology tool virology

项目摘要

DESCRIPTION (provided by applicant): HIV/AIDS is a lifelong disease with global impact. Despite the development of effective therapies, there is an ongoing need to identify novel drug targets for improving the treatment of HIV infection. A poorly understood area of HIV biology is the stage in the virus infection process termed uncoating, which involves disassembly of the polymeric viral capsid from the viral core after entry into the cell. In collaboration with Pfizer Global Research and Development, we have begun to characterize the mechanism of novel small molecule HIV-1 inhibitors that target the viral capsid. Preliminary results indicate that these inhibitors block HIV-1 infection at an early stage by triggering premature uncoating of the virus in the target cell. This proposal includes a comprehensive plan involving the tools of structural biology, cell biology, and virology to define the molecular target and detailed mechanism of action of such capsid-targeting HIV-1 inhibitors. The Specific Aims are: 1. To determine the structural consequences of PF-03450074 binding to the HIV-1 capsid. 2. To determine whether PF-03450074 promotes premature HIV-1 uncoating in target cells. 3. To determine the spectrum of mutations that confers resistance to PF-03450074. 4. To determine the mechanistic basis for the effects of the cyclophilin A-CA interaction on HIV-1 sensitivity to PF-03450074. 5. To determine the molecular basis of the late-stage inhibition by PF-03450074. The proposed research will identify a novel mechanism to inhibit HIV-1 infection, will reveal the structure of the target thereby facilitating the design of lead compounds for drug development, and will reveal new insights into the biology of HIV-1 infection. PUBLIC HEALTH RELEVANCE: Effective treatment of HIV/AIDS requires the development of novel antiviral compounds that can complement the existing drug arsenal. This research project will define the mechanism of antiviral compounds acting on a novel HIV-1 target-the capsid. The studies proposed herein will facilitate the development of novel therapies and help elucidate the stage of HIV-1 infection termed uncoating.

描述（由申请人提供）：艾滋病毒/艾滋病是一种终身疾病，具有全球影响。尽管有有效的疗法发展，但仍有持续的需要确定新的药物靶标，以改善艾滋病毒感染的治疗方法。艾滋病毒生物学的一个知识较低的区域是病毒感染过程的阶段，被称为无围座，它涉及到进入细胞后从病毒核心的聚合物病毒capsID拆卸。通过与辉瑞全球研发合作，我们已经开始表征针对病毒式衣壳的新型小分子HIV-1抑制剂的机制。初步结果表明，这些抑制剂通过触发靶细胞中病毒的过早脱膜而在早期阶段阻止了HIV-1感染。该提案包括一项综合计划，涉及结构生物学，细胞生物学和病毒学工具，以定义这种靶向带状靶向的HIV-1抑制剂的分子靶标和详细的作用机理。具体目的是：1。确定PF-03450074与HIV-1帽的结合的结构后果。 2。确定PF-03450074是否促进了靶细胞中的HIV-1脱膜过座。 3。确定赋予PF-03450074抗性的突变频谱。 4。确定环磷脂A-CA相互作用对HIV-1对PF-03450074敏感性的影响的机理基础。 5。确定PF-03450074晚期抑制的分子基础。拟议的研究将确定一种抑制HIV-1感染的新机制，将揭示靶标的结构，从而促进铅化合物的设计以进行药物开发，并揭示对HIV-1感染生物学的新见解。公共卫生相关性：有效治疗艾滋病毒/艾滋病需要开发新型的抗病毒化合物，以补充现有的药物库。该研究项目将定义作用于新型HIV-1靶标（Capsid）的抗病毒化合物的机制。本文提出的研究将促进新疗法的发展，并有助于阐明所谓的HIV-1感染阶段。