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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：
10404567
负责人：
JETZE J. TEPE
金额：
$ 36.69万
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/10404567
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，目前还没有有效的治疗方法。问题：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（IDPs）的毒性信号驱动的，比如tau，它在积累时具有高度的聚集倾向。这些未折叠的IDPs除了在积累过程中趋于聚集外，还缺乏明确的结合袋，因此它们在很大程度上避开了传统药物发现设计的努力，通常被认为是“不可药物的”。在健康的体内平衡状态下，IDPs是短暂的，并且数量很少甚至无法检测到，因为IDPs被20S蛋白酶体不断地进行蛋白水解降解。然而，当IDP的产生超过其降解时（由于基因扩增、突变或其他细胞功能障碍，包括蛋白酶体功能下降），它们随后的积累可导致有害的信号传导。在所有人体器官和组织中，大脑是IDPs表达水平最高的器官之一，某些IDPs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IDPs的毒性积累，减少脑损伤并预防痴呆。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20S蛋白酶体降解来降低过表达的IDPs的毒性水平。我们将通过开发增强20S蛋白酶体活性的小分子来诱导其蛋白水解破坏，而不是用药物来抑制IDPs。这种方法不同于以往针对国内流离失所者引发的疾病的所有尝试。与健康稳态期间低至不可检测的IDPs水平一致，我们发现增强20S蛋白酶体介导的蛋白质水解对正常细胞功能的影响很小。这是科学和人类健康领域的一个未开发领域，我们将是第一个确定这项工作中这种新方法的可能性和局限性的人之一。