Capsid-Targeting HIV-1 Antivirals

描述(申请人提供)：艾滋病毒/艾滋病是一种具有全球影响的终生疾病。尽管开发了有效的治疗方法，但仍有必要确定新的药物靶点，以改进艾滋病毒感染的治疗。艾滋病毒生物学中一个鲜为人知的领域是病毒感染过程中被称为脱壳的阶段，这涉及到进入细胞后聚合病毒衣壳从病毒核心中解体。在与辉瑞全球研究和开发公司的合作下，我们已经开始表征以病毒衣壳为靶点的新型小分子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壳，在早期阶段阻止艾滋病毒-1感染。这项建议包括一个全面的计划，涉及结构生物学、细胞生物学和病毒学的工具，以确定这种衣壳靶向HIV-1抑制剂的分子靶点和详细的作用机制。具体目的是：1.确定PF-03450074与HIV-1衣壳结合的结构后果。2.确定PF-03450074是否促进HIV-1在靶细胞中的早熟脱壳。3.确定对PF-03450074产生耐药性的突变谱。4.确定亲环素A-CA相互作用影响HIV-1对PF-03450074敏感性的机制。5.确定PF-03450074晚期抑制作用的分子基础。这项拟议的研究将确定一种抑制艾滋病毒-1感染的新机制，将揭示靶标的结构，从而促进用于药物开发的先导化合物的设计，并将揭示对艾滋病毒-1感染的生物学的新见解。 公共卫生相关性：艾滋病毒/艾滋病的有效治疗需要开发新的抗病毒化合物，以补充现有的药物武库。这项研究项目将确定抗病毒化合物对新的HIV-1靶点-衣壳的作用机制。本文提出的研究将有助于开发新的治疗方法，并有助于阐明HIV-1感染的阶段，即无涂层。

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.