A novel covalent DNA-encoded chemical library (DEL) selection method was developed by utilizing o-nitrobenzyl alcohol (o-NBA), a photo-activated lysine-selective crosslinker. Covalent capture of ligand-target interactions was achieved featuring improved crosslinking efficiency and site-specificity.

Abstract

Covalent crosslinking probes have arisen as efficient toolkits to capture and elucidate biomolecular interaction networks. Exploiting the potential of crosslinking in DNA-encoded chemical library (DEL) selection methods significantly boosted bioactive ligand discovery in complex physiological contexts. Herein, we incorporated o-nitrobenzyl alcohol (o-NBA) as a photo-activated lysine-selective crosslinker into divergent DEL formats and achieved covalent capture of ligand-target interactions featuring improved crosslinking efficiency and site-specificity. In addition, covalent DEL selection was realized with the modularly designed o-NBA-functionalized mock libraries.