RATIONAL DESIGN OF ANTIVIRAL COMPOUNDS TO THE GP41 CORE

GP41 核心抗病毒化合物的合理设计

• 批准号: 6146782
• 负责人: SHIBO JIANG
• 金额: $ 29.03万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6146782
• 关键词: HIV envelope protein gp41; X ray crystallography; analog; antiAIDS agent; antiviral agents; binding sites; chemical structure function; computer simulation; conformation; drug design /synthesis /production; enzyme linked immunosorbent assay; human immunodeficiency virus 1; human tissue; hydropathy; laboratory mouse; laboratory rabbit; membrane fusion; monocyte; virus cytopathogenic effect; virus infection mechanism

The gp41 subunit of the HIV-1 envelope glycoprotein plays a major role in the fusion of viral and target cell membranes, leading to the release of the viral genetic material into the cell and to initiation of infection. The extracellular region of gp41 contains two heptad repeat (HR) regions that consist of hydrophobic sequences with high alpha-helical propensity, located adjacent to the N-terminal fusion peptide and at the C-terminus of the gp41 ectodomain, respectively. Peptides derived from the and C-terminal HR regions of gp41 have potent inhibitory activity on the membrane fusion step of HIV-1 infection. Biophysical and crystallographic studies suggest that in the fusion-active status, both regions interact with each other to form a six-helix bundle, consisting of three N-terminal and three C-terminal helices packed in the reverse direction and representing the fusion-active gp41 core structure. A conserved hydrophobic deep cavity in the coiled coil of gp41 plays an important role in stabilizing the helical-hairpin structure of the gp41 core and in membrane fusion, suggesting an attractive target for development of anti-HIV-1 agents. We hypothesize that low molecular weight organic compounds that dock into the hydrophobic cavity or bind to other sites of the and C-terminal heptad repeat regions of gp41 may interfere with the formation of the six-helix bundle of the gp41 core and block HIV-1-mediated membrane fusion. The specific aims of this project are: 1) to identify lead antiviral compounds targeted to the HIV-1 gp41 core; 2) to determine the specificity of the lead antiviral compounds interacting with constituents of the HIV-1 gp41 core; 3) to optimize the lead antiviral compounds for generating most active anti-HIV-1 agents. The long-term goal is to develop novel anti-HIV-1 drugs for chemotherapy of HIV-1 infection and AIDS.

HIV-1 包膜糖蛋白的 gp41 亚基在病毒和靶细胞膜的融合中发挥着重要作用，导致病毒遗传物质释放到细胞中并引发感染。 gp41 的胞外区包含两个七肽重复 (HR) 区域，这些区域由具有高 α 螺旋倾向的疏水序列组成，分别位于 N 端融合肽附近和 gp41 胞外域的 C 端。 源自 gp41 的 HR 区和 C 端 HR 区的肽对 HIV-1 感染的膜融合步骤具有有效的抑制活性。生物物理和晶体学研究表明，在融合活性状态下，两个区域相互作用形成六螺旋束，由三个 N 端和三个 C 端螺旋以相反方向排列组成，代表融合活性gp41核心结构。 gp41 卷曲螺旋中保守的疏水深腔在稳定 gp41 核心的螺旋发夹结构和膜融合中发挥着重要作用，这表明抗 HIV-1 药物的开发是一个有吸引力的目标。 我们假设，对接入疏水腔或与 gp41 的 C 端七肽重复区域的其他位点结合的低分子量有机化合物可能会干扰 gp41 核心六螺旋束的形成并阻断 HIV-1介导的膜融合。 该项目的具体目标是：1）确定针对 HIV-1 gp41 核心的先导抗病毒化合物； 2) 确定先导抗病毒化合物与 HIV-1 gp41 核心成分相互作用的特异性； 3) 优化先导抗病毒化合物，以产生最具活性的抗 HIV-1 药物。 长期目标是开发新型抗HIV-1药物，用于HIV-1感染和艾滋病的化疗。