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Precise Modulation of Protein Degradation by Smart PROTACs
Junfei Cheng1, Guoqiang Dong2, Wei Wang2
1Nautical Medicine Experimental Teaching Demonstration Center of Educational Institutions, Faculty of Naval Medicine, Second Military Medical University (Naval Medical University), Shanghai, 200433, People's Republic of China.
Chembiochem : a European Journal of Chemical Biology
|October 4, 2024
Summary
Smart Proteolysis-targeting chimeras (PROTACs) offer controllable protein degradation by responding to specific stimuli. These advanced PROTACs aim to overcome toxicity issues associated with conventional targeted protein degradation therapies.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Drug Discovery
Background:
- Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules for targeted protein degradation (TPD).
- Conventional PROTACs face challenges like systemic toxicity due to non-tissue-specific targeting.
- Smart PROTACs are developed for conditional and spatiotemporal control of protein degradation.
Purpose of the Study:
- To overview recent advances in smart PROTACs for controllable TPD.
- To discuss stimuli-responsive PROTACs, including those activated by tumor microenvironment, light, or X-ray radiation.
- To focus on design strategies, case studies, applications, and challenges of smart PROTACs.
Main Methods:
- Review of smart PROTAC design strategies.
- Analysis of stimuli-responsive mechanisms (tumor microenvironment, photo-, X-ray radiation).
- Case studies illustrating controllable TPD via smart PROTACs.
Main Results:
- Smart PROTACs enable precise control over protein degradation.
- Stimuli-responsive PROTACs mitigate off-target effects and toxicity.
- Demonstrated potential for targeted therapeutic interventions through conditional degradation.
Conclusions:
- Smart PROTACs represent a significant advancement in targeted protein degradation.
- These molecules offer enhanced safety and efficacy profiles for drug discovery.
- Further research into design and application will expand their therapeutic utility.
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