Palladium Oxidative Addition Complexes for Peptide and Protein Cross-linking
The Pentelute Lab aims to invent new chemistry for the efficient and selective modification of proteins, to ‘hijack’ these biological machines for efficient drug delivery into cells and to create new machines to rapidly and efficiently manufacture peptides and proteins.
Pentelute Lab, Chemistry, MIT, Chemistry Department, Boston, Cambridge, Biology, Peptides, Peptide, Proteins, Science, Rapid, Brad Pentelute, Brad,
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Palladium Oxidative Addition Complexes for Peptide and Protein Cross-linking

Palladium Oxidative Addition Complexes for Peptide and Protein Cross-linking

J. Am. Chem. Soc., 2018, 140 (8), pp 3128–3133
DOI: 10.1021/jacs.8b00172
Publication Date (Web): February 6, 2018

Koji Kubota‡, Peng Dai‡ , Bradley L. Pentelute* , and Stephen L. Buchwald*


A new method for cysteine–lysine cross-linking 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 cross-link. The linkage so formed is stable toward acid, base, oxygen, and external thiol nucleophiles. This method was applied to cross-link cysteine with nearby lysines in sortase A*. Furthermore, we used this method for the intermolecular cross-linking 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 cross-linking techniques for peptides and proteins with natural amino acid residues.

2018, Publications