INHIBITORS OF GP41 MEDIATED HIV-1 MEMBRANE FUSION

该提议的目标是利用重组人胚肾细胞的gp 41亚基的结构， HIV包膜糖蛋白，以发现小分子抑制剂， gp 41的膜融合活性。有证据表明，受体和共- HIV-1 ENV的gp 120亚单位与受体结合， 导致膜融合活性构象的构象变化 gp 41亚基。我们和其他人已经确定了 在缺乏gp 120时表达的gp 41的可溶性胞外域， 提供了膜融合活性构象的原子模型， gp41。报道的肽类膜融合抑制剂的一个新特征， HIV-1的一个重要特征是，它们似乎针对的是一种短暂的状态， gp 41的构象变化为双层螺旋结构 通过晶体学观察。因此，预期抑制剂不会 结合X射线晶体学观察到的最终结构， 通过外层埋置在该结构中的芯线圈的一部分 螺旋我们提出了一个基于结构的设计策略和设计 一个有偏向的组合文库， 阻止外层螺旋与核心对接的抑制剂 GP 41的卷曲螺旋。我们提出的一个创新是为了研究 抑制剂的状态是产生稳定的抑制剂靶点（而不是瞬时的 通过删除外层螺旋的小部分， 芯线圈的目标部分。然后将结合的抑制剂 通过X射线晶体学可视化，以允许结合亲和力的细化。

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.