Professor of Synthetic Chemistry, ETH Zurich
Chemical Protein Synthesis with the KAHA Ligation
The chemical synthesis of proteins is a powerful tool for elucidating biological processes and has great potential for the preparation of the next generation of therapeutic proteins. Solid phase peptide synthesis (SPPS) can routinely provide peptide segments of about 40 amino acid residues but is not suited for the preparation of proteins. Our group has developed a chemoselective amide-forming reaction of -ketoacids and hydroxylamines (KAHA ligation), enabling the synthesis of proteins up to ~200 residues by combining unprotected peptide segments – without coupling reagents or side chain protecting groups.
By establishing robust, scalable routes to the key linkers and building blocks, we can now routinely synthesize small proteins using Fmoc-SPPS – without the need for any non-standard workflows or post synthesis manipulations. Orthogonal protecting groups allow convergent protein synthesis in any direction, facilitating access to a wide variety of targets including peptide therapeutics, synthetic enzymes, membrane-associated proteins, and molecular probes for biological processes.
Reference: Bode, J. W. "Chemical Protein Synthesis with the α-Ketoacid–Hydroxylamine Ligation" Acc. Chem. Res. 2017, 50, 2104–2115
Dr. Bode leads the Bode Group at ETH Zurich, which develops innovative new methods for the synthesis of organic molecules and applies these to contemporary problems in pharmaceutical development, chemical biology, and materials science.