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

针对淀粉样蛋白疾病的 α-片层化合物的设计和表征

基本信息

批准号：
9066715
负责人：
VALERIE D DAGGETT
金额：
$ 29.36万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-06 至 2018-05-31
项目状态：
已结题

项目摘要

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 α-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, Aß(1-42), amylin, and the prion protein. The specific aims of this project are: (1) Design small, stable α-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 α-sheet.

描述（由适用提供）：神经退行性疾病摧毁了全球数百万患者。这些疾病通常针对老年人。在大约50年的时间里，全世界将超过65岁。发达国家增长最快的人口组是85岁及以上的人。该人获得这些疾病之一的可能性很高（> 50％，随着年龄的增长而增加）。除了减轻症状外，这些疾病目前是不可治疗的，并且在死亡前不能明确诊断出这些疾病。这些疾病是由于蛋白质构象变化引起的，涉及形成有毒的固体聚集体。实验研究无法阐明这种结构。但是，计算机模拟为该状态提供了原子分辨率模型，发现不同蛋白质在淀粉样变性过程中形成相同的稀有结构。此结构是针对潜在的治疗和诊断剂的设计的。具体而言，该建议的重点是设计稳定的α-片结构，其生物物理表征以及在溶液中聚集期间与淀粉样蛋白蛋白的结合（以测试其抑制过程的能力）以及固定设计的化合物时（以测试其诊断能力）。设计的化合物将针对各种肽/蛋白质系统进行测试，包括经甲状腺素蛋白，Aß（1-42），淀粉素和蛋白质。该项目的具体目的是：（1）设计小的，稳定的α-片辣椒/发夹；（2）测试设计肽在溶液中抑制淀粉样蛋白形成的能力；（3）将设计固定在琼脂糖珠上，并测试设计肽结合有毒低聚物的能力；（4）表征设计的结构特性，并确定α-片的光谱特征。