以蛋白水解靶向嵌合体（PROTAC）技术为代表的事件驱动双功能分子已成功应用于降解许多感兴趣的蛋白质（POI）。由于其独特的催化机制，PROTACs将诱导多个降解循环，直到靶蛋白被消除。
该文中，研究人员首次提出了一种通用的“连接到清除”方法来终止事件驱动的降解。与清除系统的连接由TCO修饰的树枝状大分子（PAMAM-G5-TCO）和四嗪修饰的PROTACs（Tz-PROTACs）组成。PAMAM-G5-TCO可以通过逆电子需求Diels–Alder反应快速清除细胞内游离的PROTACs，并终止活细胞中某些蛋白质的降解。
该项工作提出了一种灵活的化学敲除方法，以按需调节活细胞中POI的水平，为受控的靶蛋白降解铺平了道路。
附：英文原文
Title: Ligation to Scavenging Strategy Enables On-Demand Termination of Targeted Protein Degradation
Author: Yuhui Jin, Jing Fan, Ruyan Wang, Xuanyu Wang, Ning Li, Qidong You, Zhengyu Jiang
Issue&Volume: March 27, 2023
Abstract: Event-driven bifunctional molecules, typified by proteolysis targeting chimera (PROTAC) technology, have been successfully applied in degrading many proteins of interest (POI). Due to the unique catalytic mechanism, PROTACs will induce multiple cycles of degradation until the elimination of the target protein. Here, we propose a versatile “Ligation to scavenging” approach to terminate event-driven degradation for the first time. Ligation to the scavenging system consists of a TCO-modified dendrimer (PAMAM-G5-TCO) and tetrazine-modified PROTACs (Tz-PROTACs). PAMAM-G5-TCO can rapidly scavenge intracellular free PROTACs via an inverse electron demand Diels–Alder reaction and terminate the degradation of certain proteins in living cells. Thus, this work proposes a flexible chemical knockdown approach to adjust the levels of POI on-demand in living cells, which paves the way for controlled target protein degradation.
DOI: 10.1021/jacs.2c12809
