SMALL MOLECULE MIMETICS

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，是细胞渗透和 在艾滋病中的结果感染，是由对 T细胞表面蛋白与HIV包膜蛋白的结合 Gp120。CD4的晶体结构是已知的，而且 其与gp120的复合体近在咫尺。结构构件 在这两种蛋白质中，都已经确定了建议的 在CD4-gp120识别中发挥关键作用。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。其他组件 这项研究计划的目的是利用高分辨率X射线 CD_4/gp120复合体的晶体结构 以前的结晶学和突变分析(A)以确定 计算CD_4-gp120结合部位 建模和(B)移植CD4和gp120结合位点 环和螺旋等成分形成构象 限制性小蛋白构建以获得小蛋白 模仿并使用它们来定义最小结构， 包含来自父级的足够数量的绑定站点 保持类似相互作用的蛋白质。具体目标 该提案的主要目的是(1)利用关键的结构元素 从所述高分辨率结构的建模确定，以及 随后用小蛋白模拟物设计小分子CD4 和/或gp120拮抗剂；(2)鉴定新的抑制剂 Gp120/cd4加大有针对性的合理设计力度 1.通过筛选Sb化合物库并合成 受约束的多肽和半肽螺旋、伽马转角和β- 转到模仿库。总体而言，该项目将生产微型蛋白质 和用于蛋白质模拟的有机合成技术 建筑。 GRANTP01GM565509001 HIV-1与其主要受体CD4的相互作用是 对病毒进入目标细胞至关重要。保守的自然 HIV-1 gp120囊膜上的CD4结合位点 糖蛋白使这种相互作用成为有吸引力的靶点 干预。该计划的目标是在临床上识别 可以抑制gp120-CD4相互作用的有用化合物， 利用最新的进展来理解 Gp120-CD4结合的分子细节。众多候选人 针对gp120 CD4相互作用的抗病毒分子将 将由本计划中的所有三个项目生成。的目标是 科学的核心是理解这些凸轮之间的相互作用 人类免疫缺陷病毒(HIV-1)及其成分或 宿主细胞分子(CD4和趋化因子受体)很重要 对于HIV-1病毒的进入。这一科学核心的具体目标是：1) 建立高通量筛选试验以确定抑制物 Gp120-CD4结合；2)建立二级结合和 特异性分析以确定选择性抑制剂的分子 Gp120-CD4结合并鉴定分子靶点 化合物；3)评价候选抗病毒药物的能力 抑制HIV-1进入和细胞-细胞融合的分子；以及4) 提高HIV-1对所选择的病毒的抗药性 抗病毒分子。

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 infiltration and resultant infecting in AIDS, is driven by specific recognition of the T-cell surface protein CD4 with 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 antagonists for AIDS. Other components of this research program aim to utilize the high resolution X-ray crystal structure of the CD4/gp120 complex in concert with previous crystallographic and mutational analyses (a) to identify the binding sites in the CD4-gp120 interface by computational modeling and (b) transplant CD4 and gp120 binding site components such as form loops and helices into conformationally constrained miniprotein constructions to obtain miniprotein mimetics and use these to define the minimum structure that contains a sufficient number of binding sites from the parent protein that maintains a comparable interaction. The specific aims of this proposal are to (1) 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 antagonist; (2) identify novel inhibitors of gp120/CD4 to augment the rational design efforts of Specific Aim 1, by screening the SB compound bank 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 construction. GRANTP01GM565509001 The interaction of HIV-1 with its primary receptor, CD4, is critical for viral entry into the target cell. The conserved nature of the CD4 binding site on the HIV-1 gp120 envelope glycoprotein makes this interaction an attractive target for intervention. The goal of this Program is to identify clinically useful compounds that can inhibit the gp120-CD4 interaction, taking advantage of very recent advances in understanding the molecular details of gp120-CD4 binding. Numerous candidate antiviralmolecules directed against the gp120 CD4 interaction will be generated by all three projects in this Program. The goal of this Scientific Core is to understand the interaction of these CAMs with humanimmunodeficiency virus (HIV-1) and its components or with host cellmolecules (CD4 and chemokine receptors) important for HIV-1 entry. The specific aim of this Scientific Core are: 1) To establish high-throughput screen assays to identify inhibitors of gp120-CD4 binding; 2) To establish secondary binding and specificity assays to define molecules that are selective inhibitors of gp120-CD4 binding and to identify the molecular targets compounds; 3) To evaluate the ability of candidate antiviral molecules to inhibit HIV-1 entry and cell-cell fusion; and 4) To elevate the ability of HIV-1 to become resistant to selected antiviral molecules.