A NOVEL TARGET FOR DEVELOPING ANTI-HIV INHIBITORS

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 全球艾滋病毒疫情继续扩大，超过了先前的预测，成为人类历史上最致命的流行病之一。非裔美国妇女HIV感染率的高企要求新的医疗干预措施，以消除妇女在HIV/AIDS方面的健康差距。考虑到对目前批准的抗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。本申请的长期目标是开发一类新型抗HIV药物，代表靶向HIV-1复制周期晚期的新型化学实体。我们最近的研究表明，HIV-1 Gag和宿主细丝蛋白A（FLNa）之间存在一种新的蛋白质-蛋白质相互作用，该相互作用以富有成效的方式参与HIV-1复制周期的后期阶段。干扰的相互作用重新分配Gag亚细胞定位和抑制颗粒释放。这些数据表明，Gag-FLNa相互作用可以被开发为HIV治疗的靶点。我们假设，小的合成肽，含有结合位点的FLNa的Gag，可能会阻止特异性的Gag-FLNa相互作用，导致受损的病毒组装和释放。将进行本申请中设计的实验，通过定义Gag-FLNa相互作用的生化基础，鉴定破坏体外相互作用的候选肽，并表征候选肽对病毒组装和释放的影响，来检验该中心假设。我们的研究将提供关于逆转录病毒-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具体目标内组织的一系列实验中完成。 具体目的1：确定相互作用所需的FLNa结合位点。 具体目的2：鉴定肽候选物以在体外特异性阻断相互作用。 具体目的3：检查肽候选物对病毒组装和释放的影响。

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.