Capsid-Targeting HIV-1 Antivirals

描述（申请人提供）：艾滋病毒/艾滋病是一种全球性的终身疾病。尽管开发了有效的治疗方法，但仍然需要确定新的药物靶点来改善艾滋病毒感染的治疗。HIV生物学的一个鲜为人知的领域是病毒感染过程中被称为脱衣的阶段，这一阶段涉及病毒进入细胞后从病毒核心分解聚合病毒衣壳。通过与辉瑞全球研发部的合作，我们已经开始表征针对病毒衣壳的新型小分子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的病毒过早脱壳，在早期阶段阻断HIV-1感染。本提案包括一个综合计划，包括结构生物学、细胞生物学和病毒学工具，以确定这些衣壳靶向HIV-1抑制剂的分子靶点和详细的作用机制。具体目标是：1。确定PF-03450074结合HIV-1衣壳的结构后果。2. 确定PF-03450074是否促进靶细胞中HIV-1过早脱壳。3. 确定对PF-03450074产生抗性的突变谱。4. 确定亲环蛋白A-CA相互作用对HIV-1对PF-03450074敏感性影响的机制基础。5. 目的：确定PF-03450074晚期抑制作用的分子基础。该研究将确定抑制HIV-1感染的新机制，揭示靶点的结构，从而促进药物开发先导化合物的设计，并为HIV-1感染的生物学研究提供新的见解。

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.