Nagashima Nozomu, Ozawa Shuta, Furuta Masahiro, Oi Miku, Hori Yukiko, Tomita Taisuke, Sohma Youhei, Kanai Motomu
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Sci Adv. 2021 Mar 24;7(13). doi: 10.1126/sciadv.abc9750. Print 2021 Mar.
Protein degradation induced by small molecules by recruiting endogenous protein degradation systems, such as ubiquitin-proteasome systems, to disease-related proteins is an emerging concept to inhibit the function of undruggable proteins. Protein targets without reliable ligands and/or existing outside the cells where ubiquitin-proteasome systems do not exist, however, are beyond the scope of currently available protein degradation strategies. Here, we disclose photooxygenation catalyst that permeates the blood-brain barrier and selectively and directly degrades an extracellular Alzheimer's disease-related undruggable protein, amyloid-β protein (Aβ). Key was the identification of a compact but orange color visible light-activatable chemical catalyst whose activity can be switched on/off according to its molecular mobility, thereby ensuring high selectivity for aggregated Aβ. Chemical catalyst-promoted protein degradation can be applied universally for attenuating extracellular amyloids and various pathogenic proteins and is thus a new entry to induced protein degradation strategies.
通过将内源性蛋白质降解系统（如泛素 - 蛋白酶体系统）招募到疾病相关蛋白质上，由小分子诱导的蛋白质降解是一种新兴的抑制不可成药蛋白质功能的概念。然而，没有可靠配体和/或存在于不存在泛素 - 蛋白酶体系统的细胞外的蛋白质靶点，超出了目前可用蛋白质降解策略的范围。在此，我们公开了一种光氧化催化剂，它能穿透血脑屏障，选择性地直接降解细胞外与阿尔茨海默病相关的不可成药蛋白质——淀粉样β蛋白（Aβ）。关键在于鉴定出一种紧凑但可被橙色可见光激活的化学催化剂，其活性可根据分子流动性开启或关闭，从而确保对聚集的Aβ具有高选择性。化学催化剂促进的蛋白质降解可普遍应用于减轻细胞外淀粉样蛋白和各种致病蛋白质，因此是诱导蛋白质降解策略的新成员。
