Design and characterization of alpha-sheet compounds to target amyloid diseases

描述（由申请人提供）：神经退行性疾病困扰着全球数百万患者。这些疾病通常针对老年人。大约50年后，世界上四分之一以上的人将超过65岁。发达国家增长最快的人口群体是85岁及以上的人。所述个体具有非常高的获得这些疾病之一的概率（>50%并且随着年龄增加）。这些疾病目前无法治疗，除了减轻症状，他们不能在死亡前明确诊断。这些疾病是由于蛋白质构象变化，涉及形成有毒的可溶性聚集体。实验研究一直无法阐明这种结构。然而，计算机模拟为这种状态提供了原子分辨率模型，并且发现不同的蛋白质在淀粉样变性过程中形成相同的罕见结构。该结构在此被用于设计潜在的治疗和诊断剂。具体地说，该提案集中在稳定的半折叠结构的设计，它们的生物物理特性，以及在溶液中聚集期间与淀粉样蛋白的结合（以测试它们的能力， 抑制该过程）和当所设计的化合物被固定时（以测试它们的诊断能力）。设计的化合物将针对各种肽/蛋白质系统进行测试，包括甲状腺素运载蛋白、A？（1-42）、胰淀素和朊病毒蛋白。该项目的具体目标 为：（1）设计小的、稳定的<$-折叠肽/发夹;（2）测试所设计的肽抑制溶液中淀粉样蛋白形成的能力;（3）将设计固定在琼脂糖珠上并测试所设计的肽结合有毒寡聚体的能力;和（4）表征设计的结构特性并确定<$-折叠的光谱特征。

DESCRIPTION (provided by applicant): Neurodegenerative diseases devastate millions of patients worldwide. These diseases typically target older individuals. In roughly 50 years over a quarter of the world will be over 65 years of age. The fastest growing demographic group in the developed world is people 85 and older. Said individuals have a very high probability (>50% and increasing with age) of acquiring one of these diseases. These diseases are currently untreatable, aside from alleviating the symptoms, and they can't be definitively diagnosed before death. These diseases are due to protein conformational changes involving formation of a toxic, soluble aggregate. Experimental studies have been unable to elucidate this structure. Computer simulations have, however, provided atomic resolution models for this state, and it was found that different proteins form the same rare structure during amyloidosis. This structure is being targeted here for the design of potential therapeutic and diagnostic agents. Specifically this proposal focuses on design of stable ¿-sheet structures, their biophysical characterization, and binding to amyloidogenic proteins both during aggregation in solution (to test their ability to inhibit the process) and when the designed compounds are immobilized (to test their diagnostic ability). The designed compounds will be tested against various peptide/protein systems, including transthyretin, A¿(1-42), amylin, and the prion protein. The specific aims of this project are: (1) Design small, stable ¿-sheet peptides/hairpins; (2) Test the ability of designed peptides to inhibit amyloid formation in solution; (3) Immobilize designs on agarose beads and test the ability of designed peptides to bind toxic oligomers; and (4) Characterize the structural properties of the designs and determine the spectroscopic signatures for ¿-sheet.