STRUCTURE-BASED CD4-GP120 ANTAGONISM

这项研究的中心目标是使用 Gp120/CD4复合体和基于结构的模拟分子设计 人类细胞与HIV-1相互作用的拮抗剂 导致艾滋病的人类免疫缺陷病毒。T细胞 HIV-1的对接和进入，是中国细胞感染的主要途径 艾滋病是由T细胞表面的特定识别所驱动的 由HIV包膜蛋白gp120编码的CD4蛋白。这个 CD4的晶体结构是已知的，其晶体结构 与gp120结合的复合体近在咫尺。中的结构构件 已经确定了这两个蛋白质伙伴，它们被提议 在识别CD4-gp120中起关键作用。前进中的高点 对蛋白质参与蛋白结构的理解 病毒细胞识别与先进的技术 模仿设计现在使将结构组合成为可能 测定、建模、微型蛋白质工程和有机 合成以设计新的艾滋病拮抗剂。的具体目标 这项建议如下：(1)在 通过计算模拟现有高的CD4-gp120接口 拆分结构：(2)移植CD4和gp120结合位点 组成构象受限的小蛋白 用重组DNA和化学方法构建 获得迷你蛋白模拟物并用它们来定义最小 所需的gp120 CD4结合位点的结构信息 稳定的相互作用；(3)利用关键结构元素，如 由高分辨率结构的建模确定，并且 随后利用小蛋白模拟物，设计小分子CD4 和/或gp120拮抗剂；(4)寻找新的拮抗剂 Gp120/CD4，通过筛选来增加合理的设计努力 合成物库，并通过合成受限制的多肽和 半肽螺旋、伽马转角和β转角模拟库。 总体而言，该项目将生产微型蛋白质和有机合成 先进的蛋白质模拟构建技术 界面关键结构构件的定义 CD4-gp120复合体和艾滋病候选新药。长 术语，这里推导出的模拟策略将对设计有用 其他重要的蛋白质相互作用的拮抗剂 艾滋病，如gp41-gp120和趋化因子受体 与人类细胞-HIV-1相关的相互作用 对接和病毒入侵。

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.