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

描述（由申请人提供）：神经退行性疾病摧毁了全世界数百万患者。这些疾病通常针对老年人。在大约50年的时间里，世界上超过四分之一的人将超过65岁。在发达国家，人口增长最快的群体是85岁及以上的人。这些人患这些疾病的概率非常高（大约50%，并且随着年龄的增长而增加）。除了减轻症状外，这些疾病目前是无法治疗的，而且在死亡前无法确诊。这些疾病是由于蛋白质构象改变，形成有毒的可溶性聚集体。实验研究无法阐明这种结构。然而，计算机模拟已经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过程中形成相同的罕见结构。这种结构是设计潜在的治疗和诊断药物的目标。具体来说，本提案侧重于稳定的¿-sheet结构的设计，它们的生物物理特性，以及在溶液聚集期间与淀粉样蛋白的结合（以测试它们的能力）

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.