Sialyltransferase inhibitors: consideration of molecular shape and charge/hydrophobic interactions

In order to evaluate the importance of molecular shape of inhibitor molecules and the charge/H-bond and hydrophobic interactions, we synthesized three types of molecules and tested them against a sialyltransferase. The first type of compounds were designed as substrate mimics in which the phosphate in CMP-Neu5NAc was replaced by a non-hydrolysable, uncharged 1,2,3-triazole moiety. The second type of compound contained a 2-deoxy-2,3-dehydro-acetylneuraminic moiety which was linked to cytidine through its carboxylic acid and amide linkers. In the third type of compound the sialyl phosphate was substituted by an aryl sulfonamide which was then linked to cytidine. Inhibition study of these cytidine conjugates against Campylobacter jejuni sialyltransferase Cst 06 showed that the first type of molecules are competitive inhibitors, whereas the other two could only inhibit the enzyme non-competitively. The results indicate that although the binding specificity may be guided by molecular shape and H-bond interaction, the charge and hydrophobic interactions contributed most to the binding affinity.

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► Cytidine conjugates with non-charged linker were synthesized as Neu5Ac-CMP mimics.
► The cytidine conjugates were able to inhibit sialyltransferase competitively or non-competitively.
► Binding specificity is guided mainly by molecular shape and H-bond interaction.
► Binding affinity is contributed mostly by charge and hydrophobic interactions.