SALICYLALDEHYDE-TAGGED PEPTIDES AS LYSINE-REACTIVE, REVERSIBLE-COVALENT PROTEIN BINDERS

Incorporating electrophilic groups into small-molecule ligands or peptides is a well-known strategy for increasing their binding affinity toward target proteins. The salicylaldehyde (SA) tag reacts with the ε-amino group of lysine, a common amino-acid residue, forming stable imine bonds (10.1002/cbic.202300743). In this work, we present optimized synthetic routes of two new non-canonical α-amino acids that carry the SA tag and also a new CuAAC (copper-catalyzed azide-alkyne cycloaddition) approach that allow straightforward incorporation of the SA motif into peptide sequences, supporting the development of ligands designed to selectively engage lysine residues (10.1002/ejoc.202400229).