Peptide-inspired Competitive and allosteric inhibitors of HIV entry

受肽启发的 HIV 进入的竞争性和变构抑制剂

• 批准号: 7667724
• 负责人: IRWIN M CHAIKEN
• 金额: $ 21.32万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7667724
• 关键词: Acquired Immunodeficiency Syndrome; Affinity; Affinity Labels; Allosteric Site; Amino Acids; Bacteriophages; Binding; Binding Sites; Biological Assay; CCR5 gene; CXCR4 gene; Cell membrane; Cells; Cellular Assay; Chemokine (C-C Motif) Receptor 5; Collaborations; Computer Simulation; Crystallography; DNA Sequence Rearrangement; Exposure to; Family; Goals; HIV Entry Inhibitors; HIV Envelope Protein gp120; HIV-1; Infection; Lead; Maps; Membrane Fusion; Methods; Modeling; Modification; Molecular; Mutagenesis; Organic Chemistry; Outcome; Pathway interactions; Pattern; Peptide Library; Peptide Synthesis; Peptides; Principal Investigator; Property; Proteins; Research Design; Research Personnel; Research Project Grants; Screening procedure; Site; Structure; Therapeutic; Therapeutic Agents; Thermodynamics; Vaccines; Viral; Virus; Work; affinity labeling; base; chemokine; chemokine receptor; combinatorial; design; env Gene Products; improved; inhibitor/antagonist; microbicide; mimetics; monomer; mutant; neutralizing antibody; peptide structure; peptidomimetics; pharmacophore; programs; receptor; receptor binding; size; small molecule; tool

Principal Investigator/Program Director (Last, First, Middle): Chaikei"), Irwin M DESCRIPTION: The overarching goals of this research project are to identify mechanisms of HIV-1 cell entry antagonism and derive structure-based antagonists. HIV-1 infection is dependent on attachment and entry of the virus into host cells. Virus-cell recognition occurs through initial interactions of viral spike envelope protein, gp120, with CD4 and a co-receptor, most commonly a chemokine receptor CCR5 or CXCR4. Interactions of gp120 with these receptors induce rearrangements in gp120-gp41, leading to exposure of structural components of gp41 required for virus-host cell membrane fusion. We now know that the multiple interactions of HIV-1 gp120 influence each other cooperatively, leading to progressive structural changes from flexible unliganded states to more conformationally organized forms with matured binding sites. We believe that molecules that can bind to gp120 and disrupt receptor-induced gp120 structuring can effectively disrupt the multiple receptor and gp41 interactions of gp120, and in this way, lead to effective pathways for entry antagonism. In this part of the Program Project, we will advance a miniprotein/peptide based strategy to identify molecular compounds that can suppress gp120 receptor site binding and structuring and lead to antagonists of HIV-1 entry. There are four specific aims. Aim 1. Using miniprotein and peptide starting points, identify gp120 antagonists that inhibit binding of HIV-1 Env protein to CD4 and co-receptor sites through targeting both the conserved CD4 binding site and allosteric sites. Aim 2. Map binding sites of peptide antagonists in gp120 and use this information as a guide to design higher- potency, specific antagonists as well as to more fully elucidate neutralizing sites in gp120 as long-term targets for entry inhibition. Aim 3. Profile inhibition patterns of gp120 monomers, trimers and Env mutants with peptide antagonists, and identify structural features of env protein that limit the efficacy of peptide-derived inhibitors. Identify modified peptide inhibitors with improved inhibition profiles against trimeric forms of HIV-1 envelope. Aim 4. Convert allosteric and competitive miniprotein and peptide antagonist leads into structure-minimized antagonists of HIV-1 Env with optimized dual antagonist effects in molecular assays and optimized potencies in cell infection assays. Evaluate their potential to lead to small-molecule antagonists of entry and as functional tools to elucidate mechanisms of gp120 interactions. This project will help to identify molecular approaches to control and ultimately antagonize the cooperative interactions that drive HIV-1 cell entry. The results will help amplify protein interaction mechanisms of the virus- cell entry machine. More generally, this work will help identify methods for designing therapeutic agents for flexible protein targets known to occur in other viruses.

首席调查员/计划总监（最后，第一个，中间）：chaikei”），欧文·M（Irwin M） 描述： 该研究项目的总体目标是确定HIV-1细胞进入拮抗作用的机制和 得出基于结构的拮抗剂。 HIV-1感染取决于病毒进入宿主的附着和进入 细胞。病毒细胞识别是通过病毒尖峰包膜蛋白GP120与CD4的初始相互作用发生的 和一个共受体，最常见的是趋化因子受体CCR5或CXCR4。 GP120与这些的相互作用 受体在GP120-GP41中诱导重排，导致需要GP41的结构成分暴露 用于病毒宿主细胞膜融合。我们现在知道，HIV-1 GP120的多个相互作用会影响每个 其他合作，导致从灵活的无配合状态到更多的渐进结构变化 具有成熟结合位点的构象组织形式。我们认为可以与gp120结合的分子 破坏受体诱导的GP120结构可以有效破坏多个受体和GP41相互作用 GP120的及以这种方式导致了进入拮抗作用的有效途径。 在该计划项目的这一部分中，我们将推进基于小蛋白/肽的策略，以识别分子 可以抑制GP120受体位点结合和结构并导致HIV-1拮抗剂的化合物 入口。有四个具体目标。 AIM 1。使用小蛋白和肽起点，识别抑制HIV-1 Env的结合的GP120拮抗剂 通过靶向保守的CD4结合位点和变构位点，蛋白质到CD4和共受体位点。 AIM 2。GP120中肽拮抗剂的地图结合位点，并使用此信息作为设计更高的指南 效力，特定的拮抗剂以及更完全阐明GP120中的中和位点作为长期目标 进入抑制。 AIM 3。具有肽拮抗剂的GP120单体，三聚体和ENV突变体的特征抑制模式， 确定限制肽衍生抑制剂功效的Env蛋白的结构特征。识别修改后 具有改善对三聚体形式的HIV-1包膜的抑制剂抑制剂。 AIM 4。转化变构和竞争性的微蛋白和肽拮抗剂导致结构最小化 HIV-1 Env的拮抗剂在分子测定中具有优化的双重拮抗剂作用，并在 细胞感染分析。评估它们导致小分子的入口拮抗剂的潜力和功能 阐明GP120相互作用机制的工具。 该项目将有助于确定控制和最终对抗合作的分子方法 驱动HIV-1细胞进入的相互作用。结果将有助于扩增病毒的蛋白质相互作用机制 细胞进入机。更一般地，这项工作将有助于确定设计治疗剂的方法 柔性蛋白质靶标已知发生在其他病毒中。