Targeting Lysosomal Degradation Pathways: New Strategies and Techniques for Drug Discovery
Targeting Lysosomal Degradation Pathways: New Strategies and Techniques for Drug Discovery
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靶向溶酶体降解途径：药物发现的新策略和技术
DOI：
10.1021/acs.jmedchem.0c01689
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发表时间：
2021
影响因子：
7.3
通讯作者：
Ouyang Liang
中科院分区：
文献类型：
--
作者：
Pei Junping;Wang Guan;Feng Lu;Zhang Jifa;Jiang Tingting;Sun Qiu;Ouyang Liang
一系列靶向降解蛋白质的工具正在激励科学家开发比传统小分子药物更具优势的新药。在这些工具中，蛋白水解靶向嵌合体(PROTAC)是基于蛋白酶体的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、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起着重要作用。因此，溶酶体诱导的蛋白质降解药物可以直接调节体内蛋白质水平，达到治疗疾病的目的，为药物开发提供新的策略。基于溶酶体的降解技术具有临床翻译的潜力。本文综述了溶酶体途径的靶向策略和基于溶酶体的降解技术。此外，还介绍了基于溶酶体的降解药物，并列出了其优势和挑战。我们的努力必将促进与这项技术相关的药物的设计、发现和临床应用。
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 levelsin vivo, 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.