A NOVEL TARGET FOR DEVELOPING ANTI-HIV INHIBITORS

开发抗艾滋病毒抑制剂的新目标

• 批准号: 8173599
• 负责人: Xinhong Dong
• 金额: $ 42.76万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8173599
• 关键词: AIDS/HIV problem; African American; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Binding Sites; Biochemical; Chemicals; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Epidemic; Funding; Gagging; Grant; HIV; HIV Infections; HIV-1; High Prevalence; Human; In Vitro; Institution; Intervention; Medical; Peptides; Pharmaceutical Preparations; Recording of previous events; Research; Research Personnel; Resources; Retroviridae; Series; Source; Staging; Testing; Therapeutic; United States National Institutes of Health; Virus Assembly; Woman; Women' s Health; base; design; drug discovery; filamin; health disparity; inhibitor/antagonist; novel; particle; protein protein interaction; research study; resistant strain; synthetic peptide

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The global HIV epidemic continues to expand exceeding previous predictions and became one of the deadliest epidemics in human history. The high prevalence of HIV infection in the African-American women requests the new medical intervention toward eliminating women's health disparities in HIV/AIDS. Considering the continual emergence of HIV strains that are resistant to currently approved anti-HIV drugs, the discovery and development of new anti-HIV drugs with novel antiviral mechanisms and targets are urgently need. The long-term objective of this application is to develop a novel class of anti-HIV drugs representing novel chemical entities targeting late stages of the HIV-1 replication cycle. Our recent studies demonstrate a novel protein-protein interaction between HIV-1 Gag and host filamin A (FLNa), which is involved in late stages of the HIV-1 replication cycle in a productive manner. Disruption of the interaction redistributes Gag subcellular localization and inhibits particle release. These data suggest that the Gag-FLNa interaction could be developed as targets for HIV therapeutics. We hypothesize that small synthetic peptides, containing the binding site of FLNa for Gag, might block specifically the Gag-FLNa interaction resulting in the impaired virus assembly and release. Experiments designed in this application will be performed to test this central hypothesis by defining the biochemical basis of the Gag-FLNa interaction, identifying peptide candidates to disrupt the interaction in vitro, and characterizing the effect of peptide candidates on virus assembly and release. Our studies will provide important new information regarding retrovirus-host interactions. More importantly, our studies have a high potential impact to develop novel anti-retroviral drugs with novel targets. This application will be accomplished in a series of experiments organized within three integrated specific aims. Specific Aim 1: To define the binding site of FLNa required for the interaction. Specific Aim 2: To identify peptide candidates to specifically block the interaction in vitro. Specific Aim 3: To examine the effect of peptide candidates on virus assembly and release.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 全球艾滋病毒疫情继续扩大，超出了以前的预测，成为人类历史上最致命的流行病之一。非裔美国妇女中艾滋病毒感染的高流行率要求采取新的医疗干预措施，以消除妇女在艾滋病毒/艾滋病方面的健康差距。鉴于对目前已批准的抗HIV药物具有耐药性的HIV毒株的不断出现，迫切需要发现和开发具有新的抗病毒机制和靶点的新的抗HIV药物。这项应用的长期目标是开发一类新的抗艾滋病毒药物，代表针对HIV-1复制周期后期阶段的新化学实体。我们最近的研究表明，HIV-1 Gag和宿主细丝素A(Flna)之间存在一种新的蛋白质-蛋白质相互作用，这种作用以一种有效的方式参与了HIV-1复制周期的后期阶段。这种相互作用的中断会重新分布GAG的亚细胞定位，并抑制颗粒的释放。这些数据表明，Gag-Flna的相互作用可以作为HIV治疗的靶点。我们推测，含有Flna与Gag结合部位的小分子合成肽可能特异性地阻断了Gag-Flna的相互作用，导致病毒组装和释放受损。本申请中设计的实验将通过定义Gag-Flna相互作用的生化基础、确定在体外破坏相互作用的候选多肽以及表征候选多肽对病毒组装和释放的影响来验证这一中心假设。我们的研究将提供有关逆转录病毒-宿主相互作用的重要新信息。更重要的是，我们的研究对开发具有新靶点的新型抗逆转录病毒药物具有很高的潜在影响。这一应用将在三个综合的具体目标内组织的一系列实验中完成。 具体目标1：确定相互作用所需的Flna结合位点。 具体目标2：寻找能够特异性阻断体外相互作用的候选多肽。 特定目的3：检测候选多肽对病毒组装和释放的影响。