期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 7, 页码 3493-3507出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c01689
关键词
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资金
- National Natural Science Foundation of China [81922064, 81874290, 81803755, 81903502]
- Project of Science and Technology Department of Sichuan Province [2019JDRC0091]
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University [Z20201004]
This article discusses strategies targeting lysosomal pathways and lysosome-based degradation techniques, as well as the advantages and challenges of lysosome-based degrading drugs. These tools can directly regulate protein levels in vivo and provide new strategies for treating diseases.
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 in 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.
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