Capsid-Targeting HIV-1 Antivirals

衣壳靶向 HIV-1 抗病毒药物

• 批准号: 8418741
• 负责人: Christopher R Aiken
• 金额: $ 68.46万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8418741
• 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 Targeting; 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; 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; screening; small molecule; structural biology; tool; virology

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.

描述（由申请人提供）：艾滋病毒/艾滋病是一种具有全球影响的终生疾病。尽管开发了有效的疗法，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生物学中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，该阶段涉及进入细胞后从病毒核心解体聚合病毒衣壳。我们与辉瑞全球研发部合作，已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目标细胞中病毒的过早脱壳，从而在早期阶段阻止 HIV-1 感染。该提案包括一项涉及结构生物学、细胞生物学和病毒学工具的综合计划，以定义此类衣壳靶向 HIV-1 抑制剂的分子靶点和详细作用机制。具体目标是： 1. 确定 PF-03450074 与 HIV-1 衣壳结合的结构后果。 2. 确定 PF-03450074 是否促进靶细胞中 HIV-1 过早脱壳。 3.确定赋予PF-03450074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.确定PF-03450074后期抑制的分子基础。拟议的研究将确定一种抑制 HIV-1 感染的新机制，揭示靶点的结构，从而促进药物开发的先导化合物的设计，并将揭示对 HIV-1 感染生物学的新见解。

项目成果

Host cofactors and pharmacologic ligands share an essential interface in HIV-1 capsid that is lost upon disassembly.

宿主辅助因子和药理配体在 HIV-1 衣壳中共享一个重要的界面，该界面在分解时会丢失。

• 发表时间: 2014-10
• 影响因子: 6.7
• 作者: Price, Amanda J;Jacques, David A;McEwan, William A;Fletcher, Adam J;Essig, Sebastian;Chin, Jason W;Halambage, Upul D;Aiken, Christopher;James, Leo C
• 通讯作者: James, Leo C

HIV-1 Resistance to the Capsid-Targeting Inhibitor PF74 Results in Altered Dependence on Host Factors Required for Virus Nuclear Entry.

HIV-1 对衣壳靶向抑制剂 PF74 的耐药性导致病毒进入核所需的宿主因素的依赖性发生改变。

• 发表时间: 2015-09
• 作者: Zhou, Jing;Price, Amanda J;Halambage, Upul D;James, Leo C;Aiken, Christopher
• 通讯作者: Aiken, Christopher

Compensatory substitutions in the HIV-1 capsid reduce the fitness cost associated with resistance to a capsid-targeting small-molecule inhibitor.

HIV-1衣壳的补偿性替代降低了与针对衣壳的小分子抑制剂的抗性相关的适应性成本。

• 发表时间: 2015-01
• 作者: Shi, Jiong;Zhou, Jing;Halambage, Upul D;Shah, Vaibhav B;Burse, Mallori J;Wu, Hua;Blair, Wade S;Butler, Scott L;Aiken, Christopher
• 通讯作者: Aiken, Christopher