STRUCTURE-BASED CD4-GP120 ANTAGONISM

本研究的中心目标是使用 gp 120/CD 4复合物和基于结构的模拟物设计 人细胞与HIV-1相互作用的拮抗剂， 人类免疫缺陷病毒负责艾滋病。 t细胞 HIV-1的对接和进入，这是细胞感染的主要途径， 艾滋病，是由T细胞表面的特异性识别驱动的 HIV包膜蛋白gp 120对CD 4蛋白的作用。 的 CD 4的晶体结构是已知的， 与GP 120的复合体近在咫尺。 中的结构部件 已经鉴定了两种蛋白质伴侣， 在CD 4-gp 120识别中起关键作用。 前进的高 蛋白质参与者的分辨率结构理解 病毒细胞识别以及先进的 模仿设计现在使联合收割机结构 测定、建模、微蛋白工程和有机 设计新的艾滋病拮抗剂。 的具体目标 这一建议如下：（1）确定结合位点， CD 4-gp 120接口通过现有高 解析结构：（2）移植CD 4和gp 120结合位点 构象受限的小蛋白 通过重组DNA和化学方法构建 获得微蛋白模拟物，并使用这些来定义最小的 gp 120 CD 4结合位点的结构信息， 稳定的相互作用;（3）利用关键结构要素， 从高分辨率结构的建模确定，以及 随后是微蛋白模拟物，以设计小分子CD 4 和/或GP 120拮抗剂;（4）鉴定新的 gp 120/CD 4，以通过筛选加强合理设计工作 化合物库和通过合成受约束的肽， 半肽螺旋、γ-转角和β-转角模拟文库。 总体而言，该项目将产生微蛋白和有机合成 蛋白质模拟物构建技术，一种先进的 在接口的关键结构元素的定义 CD 4-gp 120复合物与艾滋病新药 长 长期而言，这里推导出的模拟策略将有助于设计 其他蛋白质-蛋白质相互作用的拮抗剂， 艾滋病，如gp 41-gp 120和趋化因子受体 相互作用，这也与人类细胞-艾滋病毒-1 对接和病毒进入。

The central objective of this research is to use the structure of the gp120/CD4 complex and structure-based mimetics to design antagonists of the interaction of human cells with HIV-1, the human immunodeficiency virus responsible for AIDS. T-cell docking and entry by HIV-1, a major route of cell infection in AIDS, is driven by specific recognition of the T-cell surface protein CD4 by the HIV envelope protein gp120. The crystallographic structure of CD4 is known, and that of its complex with gp120 is close at hand. Structural components in both protein partners have been identified which are proposed to play key roles in CD4-gp120 recognition. The advancing high resolution structural understanding of the protein participants in virus-cell recognition together with the advancing technology of mimetics design now make it possible to combine structure determination, modeling, miniprotein engineering and organic synthesis to design new antagonist for AIDS. The specific aims of this proposal are as follows: (1) to identify binding sites in the CD4-gp120 interface by computational modeling of existing high resolution structures: (2) to transplant CD4 and gp120 binding site components into conformationally constrained miniprotein constructions by recombinant DNA and chemical approaches to obtain miniprotein mimetics and to use these to define the minimal structural information of the gp120 CD4 binding sites needed for stable interaction; (3) to utilize key structural elements, as determined from modeling of the high resolution structure and subsequently miniprotein mimetics, to design small molecule CD4 and/or gp120 antagonists; (4) to identify novel inhibitors of gp120/CD4, to augment the rational design efforts, by screening compounds banks and by synthesizing constrained peptide and semipeptide helix, gamma-turn and beta-turn mimetic libraries. Overall, this project will yield miniprotein and organic synthetic technologies for protein mimetics constructions, an advanced definition of the key structural elements at the interface of the CD4-gp120 complex and new drug candidates for AIDS. Long term, the mimetics strategies derived here will be useful to design antagonists of other protein-protein interactions important in AIDS, such as the gp41-gp120 and chemokine receptor interactions, that also are associated with human cell - HIV-1 docking and viral entry.