A new method for cysteine-lysine crosslinking in peptides and proteins using palladium oxidative addition complexes is presented. First, a biarylphosphine-supported palladium reagent is used to transfer an aryl group bearing an O-phenyl carbamate substituent to a cysteine residue. Next, this carbamate undergoes chemoselective acyl substitution by a proximal lysine to form a crosslink. The linkage so formed is stable towards acid, base, oxygen and external thiol nucleophiles. This method was applied to crosslink cysteine with nearby lysines in sortase A*. Furthermore, we used this method for the intermolecular crosslinking between a peptide and a protein based on the p53-MDM2 interaction. These studies demonstrate the potential for palladium-mediated methods to serve as a platform for the development of future crosslinking techniques for peptides and proteins with natural amino acid residues.A new method for cysteine-lysine crosslinking in peptides and proteins using palladium oxidative addition complexes is presented. First, a biarylphosphine-supported palladium reagent is used to transfer an aryl group bearing an O-phenyl carbamate substituent to a cysteine residue. Next, this carbamate undergoes chemoselective acyl substitution by a proximal lysine to form a crosslink. The linkage so formed is stable towards acid, base, oxygen and external thiol nucleophiles. This method was applied to crosslink cysteine with nearby lysines in sortase A*. Furthermore, we used this method for the intermolecular crosslinking between a peptide and a protein based on the p53-MDM2 interaction. These studies demonstrate the potential for palladium-mediated methods to serve as a platform for the development of future crosslinking techniques for peptides and proteins with natural amino acid residues.
“Palladium Oxidative Addition Complexes for Peptide and Protein Crosslinking”, J. Am. Chem. Soc., 2018, 140, 3128-3133.
Abstract: