Salicylaldehyde-Tagged Peptides for the Reversible-Covalent Engagement of Protein Lysine Residues

The design of synthetic small drugs capable of forming a covalent bond with the target protein of interest typically aims at stabilizing the drug-protein complex and to improve the pharmacological effects. The amino acid Lysine (Lys) is highly abundant in the proteome and one of the most frequent residues on the outer structural layers of proteins. Due to this high frequency, the derivatization of synthetic ligands with aldehyde tags capable of imine bond formation with Lys ɛ-amino groups may represent a general strategy for the discovery of potent small-molecule inhibitors. Ortho-hydroxy aldehydes such as pyridoxal or salicylaldehyde (SA) derivatives have been used to form imines in aqueous media, stabilized by an intramolecular H-bond between the imine N atom and the ortho-phenolic proton. By virtue of this reactivity, SA derivatives are being installed into various classes of protein ligands, aimed at the reversible-covalent engagement of protein Lys residues. This talk will describe our recent contribution to this field, with focus on the installation of the Lys-engaging SA module into peptide ligands.