自噬–溶酶体系统靶向降解蛋白质技术研究进展

Research Progress in Targeted Protein Degradation Technology of Autophagy-Lysosome System

摘要: 在靶向蛋白降解(TPD)药物开发领域，利用泛素–蛋白酶体系统的蛋白质水解靶向嵌合体(PROTACs)得到了广泛的研究。然而，泛素–蛋白酶体系统仅限于降解可溶性蛋白和膜蛋白的降解，不包括聚集蛋白/细胞外蛋白和功能失调的细胞器。溶酶体作为一种替代的蛋白质降解途径，既可通过自噬–溶酶体途径，降解细胞内靶点：如可溶性蛋白和聚集蛋白；又能通过核内体–溶酶体途径，降解细胞外靶点：如膜蛋白和分泌的细胞外蛋白。本文中，我们重点介绍新兴的溶酶体介导的靶向降解技术，如AUTAC、ATTEC、AUTOTAC、LYTAC和MoDE-A。

Abstract: In the field of Targeted Protein Degradation (TPD) drug development, Protein Targeting Chimeras (PROTACs) utilizing the ubiquitin-proteasome system have been extensively studied. However, the ubiquitin-proteasome system is limited to the degradation of soluble and membrane proteins and does not include aggregated proteins/extracellular proteins and dysfunctional organelles. Lysosomes, as an alternative protein degradation pathway, can degrade intracellular targets through the autophagy-lysosome pathway, such as soluble proteins and aggregated proteins, and can also degrade extracellular targets through the endolysosome-lysosome pathway, such as membrane proteins and secreted extracellular proteins. In this article, we focus on emerging lysosome-mediated targeted degradation techniques, such as AUTAC, ATTEC, AUTOTAC, LYTAC, and MoDE-A.