Proximity-induced amino-yne reaction for selective MDM4 conjugation via propargylated sulfonium

Whilst most bioorthogonal reactions focus on targeting binding-site cysteine residues, proximity-induced reactivity effect ensures that reaction also occurs at nucleophilic lysine residues. We report one example here that the propargylated-sulfonium center undergoes a nucleophilic reaction with lysine residue via proximity-induced conjugation. This propargylated-sulfonium tethered peptide resulting from a facile propargylation of thiolethers, enables amino-yne reaction at the selected lysine on MDM4 protein. This strategy represents a viable approach of lysine-targeted covalent inhibition in proximity. (C) 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.

Automated summary

This study presents a novel bioorthogonal reaction that occurs at lysine residues through proximity-induced reactivity, providing a viable approach for lysine-targeted covalent inhibition in proteins.