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From Transient to Stable: Incorporating Electrophiles in Genetically-Encoded and DNA-Encoded Libraries of
James H Walker1, Kejia Yan1, Ratmir Derda1
1Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
Covalent genetically encoded libraries (cGELs) enable discovery of peptide-derived macrocycles targeting previously undruggable proteins. These advanced platforms utilize persistent electrophilic warheads for selective covalent inhibition, expanding therapeutic possibilities.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Biotechnology
Background:
- Peptide-derived macrocycles are a promising therapeutic class targeting protein-protein interactions.
- Genetically encoded library (GEL) platforms accelerate discovery but have limitations in chemical space expansion.
- Electrophiles can be incorporated into GELs to create covalent ligands or facilitate cyclization.
Purpose of the Study:
- To review advances in covalent genetically encoded libraries (cGELs).
- To highlight strategies for embedding persistent electrophilic warheads in GELs.
- To discuss opportunities for discovering ligands against undruggable targets.
Main Methods:
- Phage and mRNA display platforms for GEL construction.
- Incorporation of electrophiles for covalent ligand generation.
- Development of strategies for persistent electrophilic warheads.
Main Results:
- Persistent electrophilic warheads enable selective covalent inhibition of proteins.
- Approaches yield both reversible and irreversible covalent inhibitors.
- Challenges include balancing electrophile reactivity and library integrity.
Conclusions:
- cGELs represent a significant advancement in drug discovery.
- These platforms offer new avenues for targeting historically undruggable proteins.
- Future opportunities lie in optimizing cGELs for diverse therapeutic applications.
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