We have developed a protein labelling method that consists in the selective and kinetically controlled conjugation on lysine residues exposed on the surface of the protein near the binding site of the ligand.

This approach is based on biorthogonal Cu-catalysed click-chemical reactions, in which a fast triazole synthesis from a chemically stable azide and alkyne components results in an N- or S- diversely substituted imino or thiosugar ligand library. The protein affinity of the sugar-like ligand with a short-lived NHS-ester group directs the chemical reaction on a terminal amino group of a specific lysine in the native protein.

This results in a practical chemical method for the selective covalent labelling of wild type proteins without requiring previous genetic or chemical modification of the protein backbone. Its modularity allows the application of this concepts to multiple proteins and ligands.

This method can have application in biotechnology, enzymology and diagnostic methods, as well as in the emerging sector of therapeutic antibodies and biological drugs.