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起主要作用，导致病毒遗传材料释放到细胞中并引发感染。 GP41的细胞外区域包含两个七个重复（HR）区域，这些区域由疏水序列组成，具有高α-螺旋倾向，分别位于N末端融合肽和GP41 EctoDomain的C-末端。 源自GP41的和C末端HR区域的肽对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，两个区域相互相互作用，形成了一个六螺旋束，由三个N端和三个C末端螺旋组成，它们沿反向方向填充并代表融合活性的GP41核心结构。 GP41的盘绕线圈中保守的疏水深腔在稳定GP41核心和膜融合中的螺旋发质结构中起着重要作用，这表明抗HIV-1代理的发展有吸引力的靶标。 我们假设低分子量有机化合物将其停靠在疏水腔中或与GP41的其他位点结合到其他位点，可能会干扰GP41核心的六螺旋束的形成，并阻止HIV-1核心HIV-1介导的膜介导的膜膜融合。 该项目的具体目的是：1）确定针对HIV-1 GP41核心的铅抗病毒化合物； 2）确定与HIV-1 GP41核心成分相互作用的铅抗病毒化合物的特异性； 3）优化用于生成大多数活性抗HIV-1药物的铅抗病毒化合物。 长期目标是开发新型的抗HIV-1药物，用于HIV-1感染和艾滋病的化学疗法。