Chemoselective peptide ligations for sustainable syntheses of therapeutic peptides and proteins

Abstract: Chemical assembly strategies for the manufacture of long therapeutic peptides typically require side-chain protected segments. In order to combine fully unprotected peptides at arbitrary amino acid junctions, we have developed new variants of the alpha-ketoacid–hydroxyl amine (KAHA) ligation. Through the construction of cyclic hydroxylamines and straightforward methods to install alpha-ketoacid onto synthetic and recombinant peptides, we have established direct routes to therapeutic peptides including tirzepatide. These chemoselective ligations proceed in sustainable solvents including DMSO/water and AcOH and can be translated to GMP manufacturing of therapeutic targets.