INHIBITORS OF GP41 MEDIATED HIV1 MEMBRANE FUSION

GP41 介导的 HIV1 膜融合抑制剂

• 批准号: 6336537
• 负责人: DON C WILEY
• 金额: $ 14.35万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6336537
• 关键词: HIV envelope protein gp41; X ray crystallography; antiAIDS agent; combinatorial chemistry; conformation; drug design /synthesis /production; drug discovery /isolation; electron microscopy; membrane fusion; peptide chemical synthesis; peptide library; protein structure; recombinant proteins; structural biology; virus infection mechanism

The goal of this proposal is to use the structure of the gp41 subunit of the HIV-envelope glycoprotein to discover small molecule inhibitors of the membrane fusion activity of gp41. Evidence indicates that receptor and co- receptor binding by the gp120 subunit of HIV-1 ENV triggers a conformational change resulting in the membrane-fusion active conformation of the gp41 subunit. We and other have determined the x-ray structure of a soluble ectodomain of gp41, expressed in the absence of gp120, that provides an atomic model for the membrane-fusion active conformation of gp41. A novel feature of reported peptidic membrane-fusion inhibitors of HIV-1 is that they appear to target a transient state during the conformational change of gp41 into the double layered helical structure observed by crystallography. Therefore, inhibitors are not expected to bind the final structure seen by x-ray crystallography, but instead to a section of a core coiled-coil buried in that structure by the outer-layer helices. We propose both a structure-based design strategy and the design of a biased combinatorial library that should discover small molecule inhibitors that block the docking the outer-layer helices to the core coiled coil of gp41. An innovation we propose in order to study the bound state of inhibitors is to create stable inhibitor targets (not transient ones) by deleting small sections of the outer-layer helices, uncovering a targeted section of the core coiled coil. Bound inhibitors will then be visualized by x-ray crystallography, to allow refine of binding affinity.

这项建议的目标是使用gp41亚单位的结构 HIV包膜糖蛋白发现小分子抑制物 Gp41的膜融合活性。有证据表明，受体和辅酶-2 HIV-1ENV的gp120亚单位与受体结合触发 导致膜融合活性构象变化的构象变化 Gp41亚基。我们和其他人已经确定了 Gp41的可溶性胞外结构域，在没有gp120的情况下表达， 提供了膜融合活性构象的原子模型 Gp41。已报道的多肽膜融合抑制剂的一个新特征 HIV-1病毒似乎针对的是一种短暂的状态 Gp41向双层螺旋结构的构象变化 通过结晶学观察到的。因此，预计抑制剂不会 将x射线结晶学看到的最终结构绑定到一个 由外层埋入该结构中的磁芯线圈的一部分 螺旋。我们提出了基于结构的设计策略和基于结构的设计 一个应该发现小分子的偏向组合文库 阻止外层螺旋与核心对接的抑制剂 Gp41盘绕线圈。我们提出的一项创新是为了研究边界 抑制剂的状态是创建稳定的抑制剂靶点(不是暂时性的 一些)通过删除外层螺旋的小部分，揭示了一个 铁芯盘绕线圈的目标截面。然后结合的抑制剂将被 通过X射线结晶学可视化，以精炼结合亲和力。