SMALL MOLECULE MIMETICS

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，这是细胞渗透的主要途径， 艾滋病的感染，是由特定的认识， T细胞表面蛋白CD 4与HIV包膜蛋白 gp120。CD 4的晶体结构是已知的， 它与GP 120的复合物就在眼前。 结构部件 在这两种蛋白质伴侣中已经鉴定出， 在CD 4-gp 120识别中发挥关键作用。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。 其他组件 这项研究计划的目的是利用高分辨率的X射线 CD 4/gp 120复合物的晶体结构与 先前的晶体学和突变分析（a）以鉴定 通过计算确定CD 4-gp 120界面中的结合位点 建模和（B）移植CD 4和gp 120结合位点 组分例如形成环和螺旋， 限制性微蛋白构建以获得微蛋白 模仿并使用这些来定义最小结构， 含有来自亲本的足够数量的结合位点 蛋白质，保持可比较的相互作用。具体目标 （1）利用关键结构要素， 从所述高分辨率结构的建模确定，以及 随后用微蛋白模拟物设计小分子CD 4 和/或gp 120拮抗剂;（2）鉴定新的 gp 120/CD 4用于增强Specific Aim的合理设计工作 1.通过筛选SB化合物库， 限制性肽和半肽螺旋、γ-转角和β- 转模拟库。 总的来说，这个项目将产生微蛋白 以及蛋白质模拟物的有机合成技术 建设 GRANTP01GM565509001 HIV-1与其主要受体CD 4的相互作用是 病毒进入靶细胞的关键。 保守的本性 HIV-1 gp 120包膜上的CD 4结合位点 糖蛋白使这种相互作用成为一个有吸引力的目标， 干预 该计划的目标是在临床上识别 可抑制gp 120-CD 4相互作用的有用化合物， 利用最新的进展， gp 120-CD 4结合的分子细节。 众多候选人 针对gp 120 CD 4相互作用的抗病毒分子将 这三个项目都在这个项目中。 的目标 这个科学核心是了解这些计算机的相互作用 人类免疫缺陷病毒（HIV-1）及其成分，或 与宿主细胞分子（CD 4和趋化因子受体） HIV-1病毒进入。 该科学核心的具体目标是：1） 建立高通量筛选试验，以鉴定 gp 120-CD 4结合; 2）建立二级结合， 特异性测定以确定作为选择性抑制剂的分子 的gp 120-CD 4结合，并确定分子靶点 评价候选化合物的抗病毒能力 抑制HIV-1进入和细胞-细胞融合的分子;和4） 提高HIV-1对选择的 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.