DNA-Encoded Library Technology─A Catalyst for Covalent Ligand Discovery

The identification of novel covalent ligands for therapeutic purposes has long depended on serendipity, with dedicated hit finding techniques emerging only in the early 2000s. Advances in chemoproteomics have enabled robust characterization of putative drugs to derisk the unique liabilities associated with covalent hit molecules, leading to a renewed interest in this targeting modality. DNA-encoded library (DEL) technology has similarly emerged over the past two decades as a highly efficient method to identify new chemical equity toward protein targets of interest. A number of commercial and academic groups have reported methods in covalent DEL synthesis and hit identification; however, it is evident that there is still much to be done to fully realize the power of this technology for covalent ligand discovery. This perspective will explore the current approaches in covalent DEL technology and reflect on the next steps to advance this field.