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Targeted Protein Degradation via Lysosomes
Rishi R Paudel1, Dong Lu1, Sandipan Roy Chowdhury1
1Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, Texas 77030, United States.
Biochemistry
|September 21, 2022
Summary
Lysosome-mediated targeted protein degradation offers a novel approach beyond proteasomes, enabling the clearance of aggregated proteins and organelles. This review explores emerging lysosome-targeting strategies for broader therapeutic applications.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Targeted protein degradation (TPD) primarily utilizes the ubiquitin-proteasome system (UPS).
- UPS-based TPD, including proteolysis-targeting chimeras (PROTACs), is limited to soluble and membrane proteins.
- Aggregated proteins, extracellular proteins, and dysfunctional organelles are inaccessible to UPS-mediated degradation.
Purpose of the Study:
- To review emerging lysosome-mediated targeted protein degradation strategies.
- To highlight the potential of lysosomes as an alternative degradation pathway for previously undruggable targets.
- To provide a comprehensive overview of lysosome-targeting modalities and their mechanisms.
Main Methods:
- Review of scientific literature on lysosome-mediated TPD.
- Analysis of emerging technologies like AUTAC, ATTEC, AUTOTAC, LYTAC, and MoDE-A.
- Summary of autophagy mechanisms, monitoring assays, and chemical probes.
Main Results:
- Lysosomes can degrade intracellular targets (aggregated proteins, organelles) via autophagy-lysosome pathway.
- Lysosomes can degrade extracellular targets (membrane, secreted proteins) via endosome-lysosome pathway.
- Various chemical modalities are being developed to hijack lysosomal pathways for TPD.
Conclusions:
- Lysosome-mediated TPD expands the scope of targeted degradation beyond UPS limitations.
- Emerging lysosome-targeting strategies offer new therapeutic avenues for diverse diseases.
- Further research into autophagy regulation and chemical probes will advance lysosome-mediated TPD.
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