Department of Biochemistry & Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea.
Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Korea.
Chem Soc Rev. 2024 Apr 2;53(7):3253-3272. doi: 10.1039/d3cs00344b.
Targeted protein degradation (TPD) has been established as a viable alternative to attenuate the function of a specific protein of interest in both biological and clinical contexts. The unique TPD mode-of-action has allowed previously undruggable proteins to become feasible targets, expanding the landscape of "druggable" properties and "privileged" target proteins. As TPD continues to evolve, a range of innovative strategies, which do not depend on recruiting E3 ubiquitin ligases as in proteolysis-targeting chimeras (PROTACs), have emerged. Here, we present an overview of direct lysosome- and proteasome-engaging modalities and discuss their perspectives, advantages, and limitations. We outline the chemical composition, biochemical activity, and pharmaceutical characteristics of each degrader. These alternative TPD approaches not only complement the first generation of PROTACs for intracellular protein degradation but also offer unique strategies for targeting pathologic proteins located on the cell membrane and in the extracellular space.
靶向蛋白降解（TPD）已被确立为一种可行的替代方法，可在生物和临床环境中减弱特定感兴趣蛋白的功能。独特的 TPD 作用模式使得以前不可成药的蛋白成为可行的靶标，扩展了“可成药”特性和“特权”靶标蛋白的范围。随着 TPD 的不断发展，一系列创新策略已经出现，这些策略不依赖于招募 E3 泛素连接酶，如在蛋白水解靶向嵌合体（PROTACs）中。在这里，我们概述了直接与溶酶体和蛋白酶体结合的方式，并讨论了它们的观点、优势和局限性。我们概述了每种降解剂的化学组成、生化活性和药物特性。这些替代 TPD 方法不仅补充了第一代用于细胞内蛋白降解的 PROTACs，而且还为靶向位于细胞膜和细胞外空间的病理蛋白提供了独特的策略。
