Chemistry; drug platforms

A method for linking methionine residues to small molecules could be used to generate novel therapeutic protein-drug conjugates. The method involves two steps: adding a diazo-iodonium salt to a protein or peptide in the presence of thiourea and formic acid to convert methionine’s thioether group into a diazo-sulfonium ion; and using a photocatalyzed chemical reaction to reduce the ion to a stable final product, or to link additional functional groups to the ion. When applied to Byetta exenatide, lactalbumin α (LALBA), ubiquitin and six other peptides and proteins and using an ethyl ester-based diazo-iodonium salt, the first step of the method generated ethyl ester-containing sulfonium ions on the peptides/proteins in less than five minutes with yields of up to 95%. When applied to Byetta using diazo-iodonium salts containing a range of ester functional groups, the method yielded the corresponding ester-containing sulfonium ions with yields up to 95%. In the second step of the reaction, the ethyl ester-containing sulfonium ions of Byetta, glucagon (GCG) and thioredoxin were converted to a range of small molecule conjugates with yields of up to 95%. Next steps include identifying additional chemical species that can be conjugated to the sulfonium ions (see “M is for Chemoproteomic Momentum”)...