INHIBITORS OF GP41 MEDIATED HIV1 MEMBRANE FUSION

GP41 介导的 HIV1 膜融合抑制剂

基本信息

批准号：
6631266
负责人：
DON C WILEY
金额：
$ 10.66万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-08-01 至 2003-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6631266
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

项目摘要

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.

该提案的目标是利用 gp41 亚基的结构 HIV包膜糖蛋白发现小分子抑制剂 gp41 的膜融合活性。有证据表明受体和共 HIV-1 ENV 的 gp120 亚基与受体结合会触发构象变化导致膜融合活性构象 gp41 亚基。我们和其他人已经确定了 X 射线结构 gp41 的可溶性胞外域，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。已报道的肽膜融合抑制剂的一个新特征 HIV-1 的特点是它们似乎针对的是一个短暂的状态 gp41构象变化为双层螺旋结构通过晶体学观察。因此，抑制剂预计不会结合X射线晶体学看到的最终结构，而是结合到被外层埋在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设计应该发现小分子的有偏组合库阻止外层螺旋与核心对接的抑制剂 gp41 的盘绕线圈。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目标（不是短暂的那些）通过删除外层螺旋的小部分，发现核心线圈的目标部分。结合的抑制剂将是通过 X 射线晶体学可视化，以细化结合亲和力。