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Small molecule induced proteolytic destruction of intrinsically disordered proteins

小分子诱导内在无序蛋白质的蛋白水解破坏

基本信息

批准号：
10621688
负责人：
JETZE J. TEPE
金额：
$ 5.72万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2024-01-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10621688
关键词：
Age Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Binding Biochemical Biological Assay Brain Brain Injuries Calmodulin Catalytic Domain Cell Culture Techniques Cell physiology Cells Chronic Data Dementia Disease Dose Drug Design Fibroblasts Functional disorder Future Gene Amplification Goals Guidelines Health Homeostasis Human In Vitro Lead Link Mediating Methods Modeling Mutation Neuraxis Neurodegenerative Disorders Neurons Neurosciences Organ Parkinson Disease Pathogenesis Pathogenicity Pharmaceutical Chemistry Pharmaceutical Preparations Photoaffinity Labels Positioning Attribute Production Protein Overexpression Proteins Proteolysis Proteomics Regulation Science Signal Transduction Signaling Protein Site-Directed Mutagenesis TP53 gene Testing Therapeutic Tissues Toxicology Work alpha synuclein cancer therapy cytotoxicity design drug discovery effective therapy human disease improved in vivo evaluation insight multicatalytic endopeptidase complex novel strategies novel therapeutic intervention overexpression prevent proteostasis small molecule suicide inhibitor symptom management tau Proteins tau-1 treatment duration

项目摘要

The significance: There are still no effective treatments for Alzheimer’s disease and Alzheimer’s disease related dementias. The problem: The pathogenesis of Alzheimer’s disease is driven in large part by the toxic signaling of amassed intrinsically disordered proteins (IDPs), such tau, which has a high tendency to aggregate upon accumulation. In addition to its tendency to aggregate upon accumulation, these unfolded IDPs lack defined binding pockets, thus they have largely evaded traditional drug discovery design efforts and are often deemed “undruggable”. During healthy homeostasis, IDPs are short-lived and in low-to-undetectable quantity, because IDPs are unremittingly proteolytically degraded by the 20S proteasome. However, when IDP production outpaces its degradation (due to gene amplification, mutation or other cellular dysfunctions including a decrease in proteasome function), their subsequent accumulation can lead to harmful signaling. Of all human organs and tissues, the brain expresses one of the highest levels of IDPs, and over-expression of certain IDPs have been directly linked to these neurodegenerative disorders. The solution: Recent ground breaking studies found that enhancing proteasome activity can prevent toxic accumulation of IDPs, reduce brain damage and prevent dementia. Our approach: Our hypothesis is that we can reduce toxic levels of over-expressed IDPs by enhancing/restoring 20S proteasomal degradation using small molecules. Instead of inhibiting IDPs with a drug, we will induce their proteolytic destruction by developing small molecules that enhance 20S proteasome activity. This approach is different from all previous attempts to target IDP-instigated diseases. Consistent with the low-to-undetectable levels of IDPs during healthy homeostasis, we found that enhancing 20S proteasome-mediated proteolysis has a minimal effect on normal cellular functions. This is an unexplored field in science and human health and we will be one of the first to determine the possibilities and limitations of this new approach in this work.

意义：对于阿尔茨海默病和阿尔茨海默病相关的痴呆症仍然没有有效的治疗方法。问题是：阿尔茨海默病的发病机制在很大程度上是由积累的内在无序蛋白（IDP）（例如tau）的毒性信号传导驱动的，所述tau在积累时具有高度聚集倾向。除了其在积累时聚集的趋势之外，这些未折叠的IDP缺乏限定的结合口袋，因此它们在很大程度上避开了传统的药物发现设计工作，并且通常被认为是“不可用药的”。在健康的体内平衡期间，IDP是短暂的并且处于低至不可检测的量，因为IDP被20 S蛋白酶体持续地蛋白水解降解。然而，当IDP产生超过其降解（由于基因扩增，突变或其他细胞功能障碍，包括蛋白酶体功能降低）时，它们随后的积累可能导致有害的信号传导。在所有人体器官和组织中，大脑表达最高水平的IDP之一，某些IDP的过度表达与这些神经退行性疾病直接相关。解决方案：最近的突破性研究发现，增强蛋白酶体活性可以防止IDP的毒性积聚，减少脑损伤并预防痴呆症。我们的方法：我们的假设是，我们可以通过使用小分子增强/恢复20 S蛋白酶体降解来降低过表达IDP的毒性水平。我们将通过开发增强20 S蛋白酶体活性的小分子来诱导其蛋白水解破坏，而不是用药物抑制IDP。这一做法不同于以往针对国内流离失所者引发的疾病所作的所有努力。与健康稳态期间低至不可检测水平的IDP一致，我们发现增强20 S蛋白酶体介导的蛋白水解对正常细胞功能的影响最小。这是科学和人类健康领域中一个尚未探索的领域，我们将是第一批确定这项工作中这种新方法的可能性和局限性的人之一。