Small molecule induced proteolytic destruction of intrinsically disordered proteins

意义：仍然没有有效的治疗阿尔茨海默病和阿尔茨海默病相关痴呆症的方法。问题：阿尔茨海默病的发病机制在很大程度上是由聚集的固有无序蛋白(IDPs)的有毒信号驱动的，例如tau，它有很高的聚集趋势。除了在积累后聚集的倾向外，这些展开的国内流离失所者缺乏明确的捆绑口袋，因此它们在很大程度上避开了传统的药物发现设计努力，经常被认为是“无法下药的”。在健康的动态平衡期间，国内流离失所者的寿命很短，数量很少，甚至无法检测到，因为国内流离失所者被20年代的蛋白酶体坚持不懈地降解蛋白质。然而，当IDP的产生超过其降解的速度时(由于基因放大、突变或其他细胞功能障碍，包括蛋白酶体功能下降)，它们随后的积累可能会导致有害的信号传递。在人类所有的器官和组织中，大脑表达的IDPs水平最高，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国内流离失所者的有毒蓄积，减少脑损伤和预防痴呆症。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20S蛋白酶体的降解来降低过度表达的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他们的蛋白分解破坏，而不是用药物来抑制国内流离失所者。这一方法不同于以前所有针对境内流离失所者煽动的疾病的尝试。与健康动态平衡期间低到无法检测到的IDPs水平一致，我们发现加强20S蛋白酶体介导的蛋白分解对正常细胞功能的影响最小。在科学和人类健康领域，这是一个尚未探索的领域，我们将是第一批确定这一新方法在这项工作中的可能性和局限性的人之一。

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.