Imidazolium-based warheads strongly influence activity of water-soluble peptidic transglutaminase inhibitors

• Peptidic water-soluble inhibitors incorporating imidazolium scaffold are reported.
• Inhibition was extremely sensitive to modifications of the imidazolium moieties.
• Various modulations suggested a bent conformation for the active inhibitors.
• Enzyme inhibition is reported for both tissue transglutaminase and factor.

New peptidic water-soluble inhibitors are reported. In addition to the carboxylate moiety, a new polar warhead was explored. Depending on the size of its substituents, the newly appended imidazolium scaffold designed to enhance the hydrophilic character of the inhibitors could induce a good inhibition for tissue transglutaminase (TG2) and blood coagulation factor XIIIa (FXIIIa). Correlated with the narrow tunnel that hosts the target catalytic cysteine residue, the various modulations suggest a bent conformation of the ligands as the binding pattern mode. Analogues in the dialkylsulfonium series were also tested and showed specificity for TG2 over FXIIIa.

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