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Biochemists may soon find themselves reaching for palladium reagents—chemicals once thought to be exclusively used in organic synthesis—to couple small molecules, such as drugs, onto proteins. Chemists at MIT have developed a reaction that selectively adds aryl groups to free cysteine residues in proteins. The reaction can be used to make myriad modified proteins, including therapeutic antibody-drug conjugates.

Palladium compounds have long been workhorse reagents for coupling components of small molecules. But they haven’t found much use in similar coupling reactions with proteins because they tend not to work under the particular conditions the biomolecules require: aqueous solution, low temperature, and mild pH.

Now, Bradley L. Pentelute, who specializes in bioconjugation chemistry, and Stephen L. Buchwald, an expert in palladium coupling chemistry, have combined forces to come up with a simple method to modify proteins with palladium reagents (Nature 2015, DOI: 10.1038/nature15739). Other chemists have previously used the metal to modify proteins, but these reactions required unnatural amino acids or the addition of functional groups to natural amino acids.

The reaction the Pentelute and Buchwald groups came up with uses an aryl palladium reagent to couple an aryl group selectively onto the sulfur of a cysteine residue. The reaction quantitatively modifies a protein’s free cysteine residues in a matter of minutes at room temperature in aqueous solution with 5% organic cosolvent. The resulting cysteine-modified proteins are quite stable.

The MIT chemists used the reaction to prepare several modified biomolecules, including a degradation-resistant type of peptide called a stapled peptide and a conjugate between an antibody and the anticancer drug vandetanib.

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The key to the reaction’s success, says Ekaterina V. Vinogradova, one of the lead authors on the paper, is its speed. The reaction between the palladium and the cysteine’s sulfur happens so quickly that there’s no time for other competing reactions to take place. “We never expected that the reaction would be so fast and robust,” Vinogradova tells C&EN. “We can basically take almost any aryl halide or aryl triflate and put it on a biomolecule.”