Chemical Models of Protein beta-Sheet Interactions

描述（由申请人提供）：该提案旨在深入了解蛋白质β片之间的相互作用，其广泛的长期目标是开发能够控制这种重要但未被充分认识的蛋白质-蛋白质相互作用的新化合物。蛋白质-薄片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代表性。蛋白质-薄片相互作用在与正常健康功能相关的许多生物过程中以及在从癌症和艾滋病到炭疽和阿尔茨海默病等疾病中发挥关键作用。

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.