Small molecule induced proteolytic destruction of intrinsically disordered proteins

意义：目前仍然没有有效的治疗神经退行性疾病的方法， 包括帕金森氏症和阿尔茨海默氏症以及与阿尔茨海默氏症相关的痴呆症。 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。 积累的内在无序蛋白（IDP）的信号传导，如α-突触核蛋白或 （磷酸化的）-tau，其具有高的寡聚化和聚集的倾向， 积累在健康的体内平衡期间，IDP在20秒内迅速降解， 蛋白酶体，因此寿命短，丰度几乎检测不到。随着年龄的增长， 蛋白酶体活性降低，IDP积累，导致毒性信号传导， 聚集，这是许多神经退行性疾病的标志。这些展开 国内流离失所者缺乏明确的约束口袋，这使得他们逃避传统的药物发现设计 因此，经常被认为是“不可抗拒的”。在所有人体器官和组织中， 大脑表达最高水平的IDPs之一，并积累了这些高度 紊乱的IDP与神经退行性疾病直接相关。没有有效 目前已有预防、停止或逆转这些疾病的治疗方法。 解决方案：增强20 S蛋白酶体活性应该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：我们将诱导他们的蛋白水解，而不是用药物抑制IDP， 杀伤性我们的假设是，我们可以通过以下方式限制国内流离失所者的有毒物质积累： 使用小分子增强/恢复20 S蛋白酶体降解。这种方法 这与以往所有针对国内流离失所者引发的疾病的尝试不同。我们的新数据显示 20 S蛋白酶体增强表现出对有毒的，高度无序的 寡聚化/聚集倾向的IDP超过其他蛋白质，仅含有无序 地区此外，我们的初步数据表明，治疗不会诱导细胞毒性， 以高剂量处理的细胞或在长期暴露于增强剂后的细胞。这是一个未开发的 科学和人类健康领域，我们将是第一个确定的可能性之一， 以及这种新方法的局限性。

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.