Small molecule induced proteolytic destruction of intrinsically disordered proteins

重要的是：目前还没有治疗神经退行性疾病的有效方法， 包括帕金森氏症和阿尔茨海默氏症以及阿尔茨海默氏症相关的痴呆。 问题：这些疾病的发病机制在很大程度上是由有毒物质驱动的 聚集的固有无序蛋白(IDP)的信号转导，如α-突触核蛋白或 (磷酸化)-tau，具有高度齐聚和聚集的倾向 积累。在健康的动态平衡期间，国内流离失所者在20多岁之前会迅速降解 蛋白酶体，因此是短暂的和几乎检测不到的丰度。随着年龄的增长， 蛋白酶体活性降低，内毒素堆积，导致有毒信号和 聚集，这是许多神经退行性疾病的特征。这些展开了 国内流离失所者缺乏明确的捆绑口袋，这使得他们逃避传统的药物发现设计 因此常常被认为是“无法下药的”。在所有人体器官和组织中， 大脑表达最高水平的国内流离失所者之一，并高度积累这些水平 紊乱的国内流离失所者与神经退行性疾病有直接联系。没有效果 目前已有预防、阻止或逆转这些疾病的治疗方法。 解决方案：增强20S蛋白酶体活性应能恢复健康的蛋白质稳态 并防止无序蛋白质的积累。 我们的方法：我们不是用药物抑制国内流离失所者，而是诱导他们的蛋白分解 毁灭。我们的假设是，我们可以通过以下方式限制国内流离失所者的有毒积累 使用小分子增强/恢复20S蛋白酶体的降解。这种方法是 与以往所有针对境内流离失所者煽动的疾病的努力不同。我们的新数据显示 20s蛋白酶体增强对有毒的、高度无序的 与其他仅含有无序的蛋白质相比，易于寡聚/聚集的IDPs 地区。此外，我们的初步数据显示，这些治疗没有引起细胞毒性。 高剂量处理的细胞或长期暴露于增强剂后的细胞。这是一个未开发的 在科学和人类健康领域，我们将是第一批确定 以及这种新方法在这项工作中的局限性。

The significance: There are still no effective treatments for neurodegenerative diseases, including Parkinson's and Alzheimer's disease and Alzheimer's related dementias. The problem: The pathogenesis of these disorders are driven in large part by the toxic signaling of amassed intrinsically disordered proteins (IDPs), such as α-synuclein or (phosphorylated)-tau, which have a high tendency to oligomerize and aggregate upon accumulation. During healthy homeostasis, IDPs are rapidly degraded by the 20S proteasome and thus are short-lived and in near undetectable abundance. As we age, proteasome activity is reduced and IDPs accumulate, leading to toxic signaling and aggregation, which are the hallmarks of many neurodegenerative diseases. These unfolded IDPs lack defined binding pockets, which made them evade traditional drug discovery design efforts and are therefore often deemed “undruggable”. Of all human organs and tissues, the brain expresses one of the highest levels of IDPs, and amassed levels of these highly disordered IDPs have been directly linked to neurodegenerative disorders. No effective treatments to prevent, stop or reverse these disorders are currently available. The solution: Enhancing 20S proteasome activity should restore healthy protein homeostasis and prevent the accumulation of disordered proteins. Our approach: Instead of inhibiting IDPs with a drug, we will induce their proteolytic destruction. Our hypothesis is that we can limit the toxic accumulation of IDPs by enhancing/restoring 20S proteasomal degradation using small molecules. This approach is different from all previous attempts to target IDP-instigated diseases. Our new data indicates that 20S proteasome enhancements exhibits selectivity towards the toxic, highly disordered oligomerization/aggregation-prone IDPs over other proteins that merely containing disordered regions. Moreover, our preliminary data shows that the treatments do not induce cytotoxicity in cells treated at high dose or following chronic exposure to the enhancers. 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.