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Reversible Covalent PROTACs: Novel and Efficient Targeted Degradation Strategy
Minghua Yuan1,2, Yanan Chu1,2, Yongtao Duan1
1Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou, China.
Frontiers in Chemistry
|July 22, 2021
Summary
Reversible covalent proteolysis targeting chimeras (PROTACs) offer enhanced potency and selectivity compared to noncovalent or irreversible PROTACs. This approach shows promise for overcoming challenges in targeted protein degradation strategies.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Chemical Biology
Background:
- Proteolysis targeting chimeras (PROTACs) are a promising therapeutic strategy utilizing target protein binding moiety, linker, and E3 ligase binder.
- Current PROTACs predominantly employ noncovalent or irreversible covalent binding, presenting limitations like weak affinity and unpredictable off-target effects.
Purpose of the Study:
- To compare noncovalent, irreversible covalent, and reversible covalent PROTACs.
- To highlight the potential of reversible covalent PROTACs for challenging target degradations.
Main Methods:
- Comparative analysis of different PROTAC binding modes.
- Literature review and discussion of PROTAC design principles.
Main Results:
- Noncovalent and irreversible covalent PROTACs exhibit drawbacks including weak binding and off-target effects.
- Reversible covalent PROTACs demonstrate potential for enhanced potency, selectivity, and duration of action.
Conclusions:
- Reversible covalent PROTACs offer significant advantages over existing PROTAC modalities.
- This approach could enable a broader range of targeted protein degradations for therapeutic applications.
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