Pei Junping, Wang Guan, Feng Lu, Zhang Jifa, Jiang Tingting, Sun Qiu, Ouyang Liang
State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.
J Med Chem. 2021 Apr 8;64(7):3493-3507. doi: 10.1021/acs.jmedchem.0c01689. Epub 2021 Mar 25.
A series of tools for targeted protein degradation are inspiring scientists to develop new drugs with advantages over traditional small-molecule drugs. Among these tools, proteolysis-targeting chimeras (PROTACs) are most representative of the technology based on proteasomes. However, the proteasome has little degradation effect on certain macromolecular proteins or aggregates, extracellular proteins, and organelles, which limits the application of PROTACs. Additionally, lysosomes play an important role in protein degradation. Therefore, lysosome-induced protein degradation drugs can directly regulate protein levels , achieve the goal of treating diseases, and provide new strategies for drug discovery. Lysosome-based degradation technology has the potential for clinical translation. In this review, strategies targeting lysosomal pathways and lysosome-based degradation techniques are summarized. In addition, lysosome-based degrading drugs are described, and the advantages and challenges are listed. Our efforts will certainly promote the design, discovery, and clinical application of drugs associated with this technology.
一系列靶向蛋白质降解工具正激励科学家研发出优于传统小分子药物的新型药物。在这些工具中，蛋白酶靶向嵌合体（PROTACs）是基于蛋白酶体技术的最具代表性的工具。然而，蛋白酶体对某些大分子蛋白质或聚集体、细胞外蛋白质和细胞器的降解作用很小，这限制了PROTACs的应用。此外，溶酶体在蛋白质降解中发挥着重要作用。因此，溶酶体诱导的蛋白质降解药物可以直接调节蛋白质水平，实现治疗疾病的目标，并为药物发现提供新策略。基于溶酶体的降解技术具有临床转化的潜力。在这篇综述中，总结了靶向溶酶体途径的策略和基于溶酶体的降解技术。此外，还描述了基于溶酶体的降解药物，并列出了其优点和挑战。我们的努力必将推动与该技术相关药物的设计、发现和临床应用。
