Although selective chemical reactions on proteins are necessary for many medical applications, the effects of different reaction media on reactivity and selectivity have not been thoroughly investigated. The Ohata laboratory has focused on the development of protein bioconjugation methods using nonaqueous media and succeeded with ionic liquids acting as solvents for selective reactions targeting alkylamine groups (i.e. lysine and N-terminal amines). This study is aimed at using other nonaqueous media for reactions between heteroaryl-alcohol compounds and aryl groups of various peptide and protein substrates, such as tryptophan residues. The design principle of the new nonaqueous bioconjugation strategies is based on the Piancatelli rearrangement. To optimize the bioconjugation reactions, we have tested numerous metal triflate and ammonium additives and noticed substantial increases in yield and reductions in reaction time. It was also observed that the new method does not function with increased concentrations of water in the reaction system, consistent with our hypothesis. The screening of various peptide substrates as well as analysis of the modified peptides through tandem mass spectrometry suggested that the reaction is specific to tryptophan residues.

Metal-promoted tryptophan-selective bioconjugation in nonaqueous medium

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