Discovery of Potent Proteasome Agonists to Improve Proteostasis

项目摘要 在维持蛋白质稳态方面的与蛋白质代谢相关的缺陷被认为是多种蛋白质代谢紊乱的主要促成因素。 包括阿尔茨海默氏症和帕金森氏症在内的退行性疾病，以及衰老本身。主要贡献 这些病理的一个因素是蛋白酶体不能跟上错误折叠的蛋白质的积累。 蛋白质，其最终积累到足以形成细胞毒性淀粉样蛋白的水平。一种治疗策略 为了对抗这一过程，开发了蛋白酶体介导的错误折叠蛋白质周转的激动剂，但 进展缓慢得令人沮丧，目前还没有真正的小分子激动剂。R21 一项提案要求支持应用新的化学和创新的筛选测定来解决这个问题 问题.如果成功的话，这个项目将为基于化学生物学的探索奠定基础， 蛋白酶体刺激在对抗各种蛋白质折叠疾病中的作用， 目前不可用。

Project Summary Age-related defects in maintaining proteostasis are thought to be major contributing factors to a variety of degenerative diseases, including Alzheimer's and Parkinson's, as well as aging itself. A major contributing factor to these pathologies is the inability of the proteasome to keep up with the accumulation of mis-folded proteins, which eventually accumulate to levels sufficient to form cytotoxic amyloids. One therapeutic strategy to combat this process is to develop agonists of the proteasome-mediated turnover of mis-folded proteins, but progress has been frustratingly slow and no bona fide small molecule agonists are currently available. This R21 proposal asks for support to apply both novel chemistry and an innovative screening assay to solve this problem. If successful, this project will set the stage for a chemical biology-based exploration of the utility of proteasome stimulation in combating a variety of protein folding diseases for which good treatment options are not currently available.