Development of Cellular HTS for 20S Proteasome Enhancers

20S 蛋白酶体增强剂的细胞 HTS 的开发

• 批准号: 10595889
• 负责人: Erika Mathes Lisabeth
• 金额: $ 38.39万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10595889
• 关键词: Address; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Binding; Biological Assay; Brain; Brain Injuries; Cell Culture Techniques; Cells; Cellular Assay; Characteristics; Chemicals; Complex; Dementia; Development; Disease; Drug Design; Enhancers; Event; Functional disorder; Gene Amplification; Goals; Grant; Homeostasis; Mediating; Methods; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Parkinson Disease; Pathogenesis; Pharmaceutical Preparations; Phase; Physiological; Press Releases; Property; Proteins; Refuse Disposal; Reporting; Series; Signal Transduction; Speed; Tauopathies; Therapeutic; United States National Institutes of Health; Work; alpha synuclein; base; cellular development; combat; design; drug discovery; effective therapy; efficacy testing; high throughput screening; lead candidate; multicatalytic endopeptidase complex; news; novel strategies; novel therapeutic intervention; overexpression; oxidative damage; prevent; screening; small molecule; superoxide dismutase 1; synucleinopathy; tau Proteins; three dimensional structure; tool; translational potential

There are still no effective treatments for neurodegenerative diseases, including Parkinson’s disease (PD), Alzheimer’s disease (AD) and Alzheimer’s related dementias (ADRD). One major obstacle in finding small molecules capable of combatting these synucleinopathies and tauopathies is that the proteins that mediate these disorders are structurally unfolded (i.e. intrinsically disordered). In addition to their tendency to aggregate upon accumulation, intrinsically disordered proteins lack defined binding pockets, thus they have largely evaded traditional drug discovery design efforts. However, recent studies found that enhancing proteasome activity can prevent toxic accumulation of intrinsically disordered proteins (such as α-synuclein and tau species), reduce brain damage and prevent AD related dementia. Of the different proteasome complexes, only the 20S proteasome targets intrinsically disordered directly for degradation. Unfortunately, the translational exploration of this entirely new therapeutic strategy has been limited due to (1) the lack of a suitable cellular assay to identify 20S proteasome enhancers and subsequently, (2) lack of drug-like small molecule 20S proteasome enhancers. This grant will directly address these two voids that currently prevent the exploration of this new therapeutic strategy to treat PD, AD and ADRDs. In the R61 phase, we will develop and validate the first cellular and physiologically relevant high throughput screening (HTS) assays with the goal to broaden the portfolio of small molecule drug-like enhancers of the 20S proteasome. In the R33 phase, we will optimize the efficacy and physiochemical properties of two select series from that screen to generate the first suitable agents for the translational exploration of this new approach. Successful completion of this work will provide a robust platform to identify and develop suitable drug-like candidates to explore the translational potential of this new therapeutic approach for treating Parkinson’s disease, Alzheimer’s disease and Alzheimer’ related dementias.

对于神经退行性疾病，包括帕金森病（PD）， 阿尔茨海默病（AD）和阿尔茨海默病相关痴呆（ADRD）。在寻找小的一个主要障碍 能够对抗这些共核蛋白病和tau蛋白病的分子是， 这些病症在结构上是未折叠的（即本质上是无序的）。除了它们聚集的趋势之外 在积累时，本质上无序的蛋白质缺乏确定的结合口袋，因此它们在很大程度上 避开了传统的药物发现设计工作。然而，最近的研究发现， 活性可以防止内在无序蛋白质（如α-突触核蛋白和tau蛋白）的毒性积累， 物种），减少脑损伤和预防AD相关痴呆症。在不同的蛋白酶体复合物中， 只有20 S蛋白酶体靶向本质上无序的直接降解。可惜 这种全新的治疗策略的转化探索受到限制，这是由于（1）缺乏 鉴定20 S蛋白酶体增强子合适的细胞测定，以及随后的，（2）缺乏药物样小分子 分子20 S蛋白酶体增强剂。 这项拨款将直接解决这两个空白，目前阻止探索这种新的治疗 治疗PD、AD和ADRD的策略。在R61阶段，我们将开发和验证第一个蜂窝和 生理学相关的高通量筛选（HTS）测定，目的是扩大小规模的 20 S蛋白酶体的分子药物样增强剂。在R33阶段，我们将优化疗效， 从筛选中选择两个系列的理化性质，以产生用于 对这种新方法的转化探索。 这项工作的成功完成将提供一个强大的平台，以确定和开发合适的药物， 候选人探索这种新的治疗方法治疗帕金森氏症的转化潜力 阿尔茨海默病和阿尔茨海默相关痴呆。