Recent advances in DNA-encoded libraries: From covalent targeting to protein profiling

DNA-encoded library (DEL) technology has enabled efficient discovery of both non-covalent and covalent inhibitors, with covalent binders typically identified via covalent DELs (CoDELs) containing diverse electrophilic warheads. Recent developments have expanded CoDEL applications beyond cysteine to residues like lysine, tyrosine, arginine, and glutamic acid. The integration of CoDEL with activity-based protein profiling (ABPP) has further enabled the identification of potential protein targets for CoDEL screening using residue-selective warheads. Additionally, proteome profiling with fully-functionalized tags has guided target identification for focused DELs with privileged structures. This review highlights recent advances in CoDEL technologies for targeting both cysteine and non-cysteine residues, and discusses how proteomics facilitates hit discovery through CoDELs and focused DELs.