Abstract：
PROTACs (Proteolysis-Targeting Chimeras) have emerged as a groundbreaking class of chemical tools that facilitate the degradation of target proteins by leveraging the ubiquitin-proteasome system (UPS). However, the effective utilization of PROTACs in chemical biology studies and therapeutics encounters significant challenges when it comes to achieving cell-selective protein degradation and in vivo applications. This review article aims to shed light on recent advancements in the development of Pro-PROTACs, which exhibit controlled protein degradation capabilities in response to external stimuli or disease-related endogenous biochemical signals. The article delves into the specific chemical strategies employed to regulate the interaction between PROTACs and E3 ubiquitin ligases or target proteins. These strategies enable spatial and temporal control over the protein degradation potential of Pro-PROTACs. Furthermore, the review summarizes recent investigations regarding the delivery of PROTACs using biodegradable nanoparticles for in vivo applications and targeted protein degradation. Such delivery systems hold great promise for enabling efficient and selective protein degradation in vivo. Lastly, the article provides a perspective on the future design of multifunctional PROTACs and their intracellular delivery mechanisms, with a particular focus on achieving cell-selective protein degradation.
摘要：
PROTACs（蛋白水解靶向嵌合体）已成为一类开创性的化学工具，可通过利用泛素-蛋白酶体系统（UPS）促进靶蛋白的降解。然而,在实现细胞选择性蛋白质降解和体内应用方面，PROTACs在化学生物学研究和治疗中的有效利用面临着重大挑战。这篇综述文章旨在阐明Pro-PROTACs开发的最新进展，其表现出响应于外部刺激或疾病相关的内源性生化信号的受控蛋白质降解能力。本文探讨了用于调节PROTACs与E3泛素连接酶或靶蛋白之间相互作用的特定化学策略。这些策略能够对Pro-PROTACs的蛋白质降解潜力进行空间和时间控制。此外，这篇综述总结了最近关于使用可生物降解的纳米颗粒进行体内应用和靶向蛋白质降解的PROTACs递送的研究。这样的递送系统对于在体内实现有效和选择性的蛋白质降解具有巨大的前景。最后,本文对多功能PROTACs的未来设计及其细胞内传递机制提供了一个观点，特别关注实现细胞选择性蛋白质降解。
