CHEMICAL MODELS OF PROTEIN BETA SHEET INTERACTIONS

蛋白质之间的β-折叠相互作用在许多 与疾病和正常功能相关的生物过程。 例子包括通过丝氨酸/苏氨酸结合RAS和RAP Raf在细胞信号和癌基因表达、二聚化中的作用 HIV蛋白水解酶的活性，以及CD4受体和 HIV病毒蛋白gp120。β-折叠的形成也参与了 多肽和蛋白质聚集形成不溶的β-折叠 这些结构与各种毁灭性的 神经疾病，包括阿尔茨海默病，Creutzfeld-Jacob 疾病和其他Pron病，以及亨廷顿氏病。 这一提议试图通过以下方式模仿和破坏测试表交互 使用的化学模型系统被称为“人造贝塔-薄片”。宽阔的， 这项研究的长期目标包括发展 治疗蛋白质间形成β-折叠的疾病的药物 (例如，癌症、亨廷顿病和阿尔茨海默病)和 开发用于产生干扰化合物的一般策略 测试页互动。具体目标如下：(1) 基于贝塔薄片的人造贝塔薄片结构 MET抑制物二聚体的两半的界面将是 合成的二聚体将被合成，其结构将被 用核磁共振和圆二色谱进行了研究。(2)人造贝塔薄片 旨在模拟Fab部分的蛋白G结合区 免疫球蛋白G的合成及其与结构域的相互作用 用核磁共振波谱对蛋白质G的三个组分进行研究。(3)人造的 设计用于模拟RAS之间的测试表界面的测试表 蛋白质和c-rafl激酶(Raf)和人造β-折叠， 模拟RAS和RAF的结合区将被合成。他们的 结构和相互作用将通过CD和核磁共振光谱进行研究， 后两种化合物将被用于抗癌活性的评估。 采用NCI对60例人肿瘤细胞株进行体外筛选。(4) 仿制聚谷氨酰胺β-折叠的人造β-折叠 与亨廷顿氏病和其他遗传疾病有关的聚集体 神经退行性疾病将被合成。他们的结构将是 用圆二色谱和核磁共振谱研究了它们的封闭能力 聚谷氨酰胺β-折叠聚集性将使用In 体外试验。(5)设计用于阻断β-淀粉样蛋白的人造β-片剂 聚合将被合成，它们阻止其 聚集和沉积将使用体外试验进行研究。

beta-Sheet interactions between proteins play a critical role in many biological processes associated with diseases and with normal function. Examples including the binding of Ras and Rap by the serine/threonine kinase Raf in cell signaling and oncogene expression, the dimerization of HIV protease, and the interaction between the CD4 receptor and the HIV viral protein gp120. beta-Sheet formation is also involved in the aggregation of peptides and proteins to form insoluble beta-sheet structures that are associated with a variety of devastating neurological disorders, including Alzheimer's disease, Creutzfeld-Jacob disease and other prion diseases, and Huntington's disease. This proposal seeks to mimic and to disrupt beta-sheet interactions by using chemical model systems called "artificial beta-sheets." The broad, long-term objectives of this research encompass both the development of drugs for diseases involving beta-sheet formation between proteins (e.g., cancer, Huntington's disease, and Alzheimer's disease) and the development for general strategies for creating compounds that disrupt beta-sheet interactions. The specific aims are as follows: (1) Artificial beta-sheet structures based upon the beta-sheet at the interface of the two halves of the met repressor dimer will be synthesized dimer will be synthesized, and their structures will be studied by NMR and CD spectroscopy. (2) An artificial beta-sheet designed to mimic the protein G binding region of the Fab portion of the immunoglobulin G will be synthesized, and its interaction with domain III of protein G will be studied by NMR spectroscopy. (3) An artificial beta sheet designed to mimic the beta-sheet interface between Ras proteins and the c-Rafl kinase (Raf) and artificial beta-sheets that mimic the binding regions of Ras and Raf will be synthesized. Their structures and interactions will be studied by CD and NMR spectroscopy, and the latter two compounds will be evaluated for anti-cancer activity by the NCI using an in vitro 60 human tumor cell line screen. (4) Artificial beta-sheets designed to mimic polyglutamine beta-sheet aggregates, which are involved in Huntington's disease and other genetic neurodegenerative diseases will be synthesized. Their structures will be studied by CD and NMR spectroscopy, and their ability to block polyglutamine beta-sheet aggregation will be determined using an in vitro assay. (5) Artificial beta-sheets designed to block beta-amyloid aggregation will be synthesized, and their abilities to block its aggregation and deposition will be studied using in vitro assays.