Overcoming proteasome impairment with small molecules

用小分子克服蛋白酶体损伤

• 批准号: 10427952
• 负责人: JETZE J. TEPE
• 金额: $ 16.79万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2024-01-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10427952
• 关键词: Address; Aducanumab; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid beta-Protein; Antibodies; Binding; Biological Assay; Cause of Death; Cells; Cellular Assay; Complex; Dementia; Dipeptides; Disease; Disease Progression; Disease model; Electron Microscopy; Enhancers; Event; Grant; Impairment; Mediating; Monitor; Monoclonal Antibodies; National Institute on Aging; Neurodegenerative Disorders; Pathogenesis; Pathogenicity; Patients; Prevention; Production; Proteins; Proteolysis; Publishing; Regulation; Research; Signal Transduction; Symptoms; Testing; Therapeutic; Validation; Western Blotting; Work; advanced disease; alpha synuclein; cytotoxic; drug discovery; early onset; effective therapy; in vitro activity; innovation; multicatalytic endopeptidase complex; neurotoxicity; novel therapeutic intervention; prevent; protein degradation; protein oligomer; restoration; small molecule; translational potential

Other than the recently approved antibody, Aducanumab, which may help early onset patients, there are no therapeutic treatments to prevent, slow or cure neurodegenerative diseases such Alzheimer's disease and related dementias (ADRD). Current treatments only temporarily suppress disease symptoms. This work aims to investigate small molecule 20S proteasome activation as a new, innovative therapeutic strategy to slow and/or prevent disease progression. Proteins such as amyloid-Beta, alpha-synuclein and dipeptide repeat units are intrinsically disordered proteins (IDPs), which have a high tendency to oligomerize and aggregate upon accumulation. The exact mechanism by which these oligomers induce neurotoxicity is complex and still debated. However, it is widely accepted that accumulation of these aggregation-prone proteins results in (1) toxic oligomeric species and (2) proteasome impairment, which are two classic hallmarks of neurodegenerative disorders that ultimately drive disease progression. In this exploratory R21 grant, we are pioneering a new paradigm in drug discovery, which is focused on preventing the accumulation of IDPs by enhancing the activity of the 20S proteasome using small molecules. Our hypothesis is that small molecule 20S proteasome enhancement will induce the degradation of IDPs, and thereby prevent and restore proteasome function, that was impaired by these IDP oligomers. To test this hypothesis, we will explore the efficacy of two new, but distinct classes of 20S proteasome enhancers, discovered and published by our research group, for their ability to (1) prevent IDP accumulation and (2) restore impaired proteasome function. Impact: According to the National Institutes of Aging, AD is the 6th leading cause of death in the US, yet it remains mostly without effective treatment options. Successful completion of this work will validate a new strategy that tackles two fundamental steps in the pathogenesis of these disorders, which may provide a therapeutic strategy to treat these devastating dementias.

除了最近批准的抗体 Aducanumab 可以帮助早发患者， 没有治疗方法可以预防、减缓或治愈神经退行性疾病，例如 阿尔茨海默病和相关痴呆症（ADRD）。目前的治疗只是暂时的 抑制疾病症状。本工作旨在研究小分子20S蛋白酶体 激活作为一种新的、创新的治疗策略来减缓和/或预防疾病进展。 β-淀粉样蛋白、α-突触核蛋白和二肽重复单元等蛋白质本质上是无序的 蛋白质（IDP），在积累时很容易寡聚和聚集。 这些寡聚物引起神经毒性的确切机制很复杂，而且仍然存在 争论了。然而，人们普遍认为这些易于聚集的蛋白质的积累 导致（1）有毒寡聚物种和（2）蛋白酶体损伤，这是两个经典的 最终推动疾病进展的神经退行性疾病的标志。 在这项探索性 R21 资助中，我们正在开创药物发现的新范式，即 重点是通过加强 20S 的活动来防止国内流离失所者的积累 使用小分子的蛋白酶体。我们的假设是小分子 20S 蛋白酶体 增强会诱导IDPs的降解，从而阻止和恢复蛋白酶体 这些 IDP 寡聚物损害了功能。为了检验这个假设，我们将探索 两种新的但不同类别的 20S 蛋白酶体增强剂的功效被发现并 由我们的研究小组发表，因其能够 (1) 防止国内流离失所者积累和 (2) 恢复 蛋白酶体功能受损。 影响：根据美国国家老龄化研究所的数据，AD 是美国第六大死因 美国，但仍然大多没有有效的治疗方案。顺利完成本次工作 将验证一项新策略，解决这些疾病发病机制中的两个基本步骤 疾病，这可能为治疗这些破坏性痴呆症提供治疗策略。