SYNTHESIS OF SALICYLALDEHYDE DERIVATIVES AS LYSINE-ENGAGING TAGS IN REVERSIBLE-COVALENT PEPTIDE LIGANDS

Ligand modification with electrophilic groups that can form a covalent bond with nucleophilic amino acid residues in a target protein can enhance binding affinity and improve the stability of the small molecule-protein complex. Lysine (Lys) residues are abundant throughout the proteome and are often found on the protein surface. Consequently, derivatizing ligands with aldehyde tags that can form imine bonds with the ε-amino groups of Lys offers an attractive approach for developing reversible-covalent binders targeting clinically-relevant proteins or protein-protein interactions. Our research group succeeded in the introduction of the Lys-engaging salicylaldehyde (SA) tag at the N- or C-terminus of a model cycloRGD peptide. However, the only SA installation at terminal peptide positions limits the scope of this approach, as many nucleophilic Lys residues may be located around the binding site, but far away from the peptide extremities. For this reason, installing the SA tag at internal peptide positions (i.e., on the side chains of α-amino acids) could offer a more versatile strategy for engaging proximal Lys residues.