Synthesis of Noncoded Amino Acids Bearing a Salicylaldehyde Tag for the Design of Reversible‐Covalent Peptides

Abstract

Insertion of electrophilic species on the structure of small molecule ligands or peptides is a well‐known strategy to increase their binding affinity for the target protein of interest. Among these reactive units, the salicylaldehyde (SA) tag can form remarkably stable imine bonds with the ε‐amino group of lysine, a highly frequent residue in proteins. In this work, we describe the optimized synthesis of two new noncoded α‐amino acids, starting from l‐homoserine and featuring the SA tag on the side chain. One of these final compounds was successfully inserted into a model tripeptide through in‐solution synthesis. These building blocks will allow the versatile insertion of the SA tag at suitable position of peptide sequences, opening to a tailored design of Lys‐engaging peptide ligands.