Chemical Models of Protein beta-Sheet Interactions

蛋白质 β-折叠相互作用的化学模型

• 批准号: 6873241
• 负责人: JAMES S NOWICK
• 金额: $ 28.59万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-04-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6873241
• 关键词: Huntington' s disease; aminoacid; aminoacid analog; amyloid proteins; analytical method; biotechnology; chemical aggregate; chemical models; combinatorial chemistry; conformation; cyclic compound; drug discovery /isolation; high performance liquid chromatography; macrophage inflammatory proteins; nerve /myelin protein; neural degeneration; nuclear magnetic resonance spectroscopy; ornithine; peptide chemical synthesis; protein binding; protein protein interaction; protein structure; recombinant DNA; small molecule; surface plasmon resonance; synthetic peptide

DESCRIPTION (provided by applicant): This proposal seeks to gain insight into interactions between protein beta-sheets, with the broad long-term objective of developing new compounds that can control this important, but underappreciated, class of protein-protein interactions. Interactions between protein beta-sheets occur widely and are represented significantly in about 15% of the protein structures in the Protein Data Bank (PDB). Protein beta-sheet interactions play a critical role in many biological processes associated with normal healthy function and in diseases ranging from cancer and AIDS to anthrax and Alzheimer's disease. The investigators will gain insight into interactions between protein beta-sheets by developing and studying chemical models of beta-sheets that bind proteins by means of beta-sheet interactions. These chemical models will be cyclic compounds containing a new amino acid building block that the investigators invented (Hao) and a new turn unit that the investigators discovered (delta-linked ornithine). The investigators will study the binding of cyclic chemical models of the CH1 domain of Fab to protein G domain III, to gain insight into interactions between protein beta-sheets and to determine what is necessary to create relatively simple chemical compounds that participate in the same types of beta-sheet interactions as much larger proteins. The investigators will use these systems and the insights gained from these studies to develop compounds that block the aggregation of beta-amyloid and Huntington, which are associated with Alzheimer's and Huntington's diseases. By developing synthetic compounds that bind to a real protein domain and bind proteins associated with important neurodegenerative diseases, these studies will further the long-term objective of creating compounds that can control interactions between protein beta-sheets. These insights and new compounds may eventually pave the way to new drugs to treat diseases and improve human health.

描述（由申请人提供）：该提案旨在深入了解蛋白质β-折叠之间的相互作用，其广泛的长期目标是开发可以控制这一重要但未被充分认识的蛋白质-蛋白质相互作用类别的新化合物。蛋白质 β-折叠之间的相互作用广泛发生，并且在蛋白质数据库 (PDB) 中约 15% 的蛋白质结构中显着存在。蛋白质β-片层相互作用在与正常健康功能相关的许多生物过程以及从癌症和艾滋病到炭疽和阿尔茨海默病等疾病中发挥着关键作用。 研究人员将通过开发和研究通过β-折叠相互作用结合蛋白质的β-折叠化学模型，深入了解蛋白质β-折叠之间的相互作用。这些化学模型将是环状化合物，包含研究人员发明的新氨基酸结构单元（Hao）和研究人员发现的新转角单元（δ-连接鸟氨酸）。研究人员将研究 Fab 的 CH1 结构域与蛋白质 G 结构域 III 的环状化学模型的结合，以深入了解蛋白质 β-折叠之间的相互作用，并确定创建参与相同类型的相对简单的化合物所需的条件β-折叠相互作用与更大的蛋白质一样。研究人员将利用这些系统以及从这些研究中获得的见解来开发阻止β-淀粉样蛋白和亨廷顿蛋白聚集的化合物，这些蛋白与阿尔茨海默病和亨廷顿病有关。 通过开发与真实蛋白质结构域结合并结合与重要神经退行性疾病相关的蛋白质的合成化合物，这些研究将进一步实现创造能够控制蛋白质β-折叠之间相互作用的化合物的长期目标。这些见解和新化合物最终可能为治疗疾病和改善人类健康的新药铺平道路。