Chemical Models of Protein beta-Sheet Interactions

描述(由申请者提供)：这项建议旨在深入了解蛋白质β-折叠之间的相互作用，其长远目标是开发能够控制这一重要但未得到重视的蛋白质-蛋白质相互作用的新化合物。蛋白质β-折叠之间的相互作用广泛存在，在蛋白质数据库(PDB)中约15%的蛋白质结构中有显著的表现。蛋白质β-折叠相互作用在许多与正常健康功能相关的生物过程中，以及在癌症和艾滋病、炭疽病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-折叠的化学模型来深入了解蛋白质β-折叠之间的相互作用。这些化学模型将是环状化合物，其中包含研究人员发明的一种新的氨基酸组成单元(HAO)和研究人员发现的一种新的转折单位(三角洲连接的鸟氨酸)。研究人员将研究FAB的CH1结构域与蛋白质G结构域III的循环化学模型的结合，以深入了解蛋白质β-折叠之间的相互作用，并确定创建相对简单的化合物所必需的条件，这些化合物参与与更大的蛋白质相同类型的β-折叠相互作用。研究人员将使用这些系统和从这些研究中获得的见解来开发出阻止与阿尔茨海默氏症和亨廷顿病有关的β-淀粉样蛋白和亨廷顿氏症聚集的化合物。 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可能最终会为治疗疾病和改善人类健康的新药铺平道路。

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.