DDR SUBPRJ 5:FLEXIBLE PEPTIDE INHIBITORS INDUCING A STABLE CONFORMATION

DDR SUBPRJ 5：诱导稳定构象的柔性肽抑制剂

• 批准号: 7715252
• 负责人: Jennifer A Edwards
• 金额: $ 11.32万
• 依托单位: FLORIDA AGRICULTURAL AND MECHANICAL UNIV
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7715252
• 关键词: Accounting; Active Sites; Affect; Anti-HIV Agents; Closure; Combined Modality Therapy; Computer Retrieval of Information on Scientific Projects Database; Data; Distant; Docking; Drug resistance; Endopeptidases; Enzymes; Funding; Goals; Grant; HIV-1 protease; Hand; Institution; Investigation; Ligand Binding; Molecular Conformation; Mutation; Object Attachment; Peptide Hydrolases; Peptides; Pliability; Point Mutation; Population; Process; Protease Inhibitor; Proteins; Range; Research; Research Personnel; Resistance; Resources; Source; Structure; United States National Institutes of Health; Viral Genome; Virus; conformer; design; inhibitor/antagonist; molecular dynamics; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Protease inhibitors for HIV-1 protease have been developed in recent years. However, a major difficulty in the treatment with anti-HIV drugs has been the rapid mutations in the viral genome that result in resistance to the drug through changes in the protein target. Combination therapies and cocktails have developed in response to the resistance of the virus to protease inhibitors. Moreover, many resistant mutations can occur distant from the active site. These observations support a mechanism for drug resistance that is not specific to each inhibitor structure. Rather, they support a mechanism that affects a dynamic process of protease closure and conformational change upon ligand binding. The central hypothesis of this application is that the proteae inhibitor should account for the dyanamic process that occurs upon ligand binding. The inibitors in this proposal have a "reduced" peptide bond and a phyenlanine group in the middle, and a naphthlylalanine on either end. We seek to prove our hypothesis through the specific aims of examining the NMR spectra of these peptides to determine their flexibility, and docking these inhibitors into HIV-1 protease performing computational molecular dynamics simulations. On the one hand, some flexibility is good in that the pepide can adapt to the active site of the enzyme in its open conformation. On the other hand, too rigid a peptide inhibitor will reduce the population of the best conformer and will be less able to adapt to the point mutations in the protease tha taffect its dynamics. The data accumulated in this investigation will lay the groundwork for the long range goals of this proposal to design more effective inhibitors that affect the dynamics of the HIV-1 protease in a manner that resist mutations in this enzyme.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 近年来已开发出针对HIV-1蛋白酶的蛋白酶抑制剂。然而，抗HIV药物治疗的一个主要困难是病毒基因组的快速突变，通过蛋白质靶点的变化导致对药物的耐药性。针对病毒对蛋白酶抑制剂的耐药性，开发了联合疗法和鸡尾酒疗法。此外，许多抗性突变可能发生在远离活性位点的地方。这些观察结果支持了一种耐药机制，该机制并非针对每种抑制剂结构。相反，它们支持一种影响蛋白酶闭合动态过程和配体结合时构象变化的机制。该申请的中心假设是蛋白酶抑制剂应该解释配体结合时发生的动态过程。该提案中的抑制剂具有“还原”肽键和中间的苯丙氨酸基团，以及两端的萘基丙氨酸。我们试图通过检查这些肽的 NMR 谱以确定其灵活性，并将这些抑制剂对接到 HIV-1 蛋白酶中进行计算分子动力学模拟来证明我们的假设。一方面，一定的灵活性是好的，因为肽可以以其开放构象适应酶的活性位点。另一方面，过于严格的肽抑制剂会减少最佳构象异构体的数量，并且不太能够适应蛋白酶中影响其动力学的点突变。这项研究中积累的数据将为该提案的长期目标奠定基础，即设计更有效的抑制剂，以抵抗这种酶突变的方式影响 HIV-1 蛋白酶的动态。