This class of non-peptidyl, active site directed molecules was developed by Merck Sharp & Dohme in the 1990s. The active site cysteinyl residue attacks the carbonyl group (1) similar to the glutamine residue. However, the subsequent reaction leads to the release of the complementary thione (2) and to the acetonylation of the cysteine (3) (Freund et al., Biochemistry 1994, 33:10109-19).
Even if the molecules were developed to block coagulation factor XIIIa, the compounds inhibit tissue transglutaminase as well (Barsigan et al., J. Biol. Chem. 1991, 22501-9).
One candidate out of the series has been evaluated in animal models (e.g. Shebuski et al., blood 1990, 1455-9). Please notice that the authors reported a plasma half life of 5 to 10 minutes only.
Zedira offers three derivatives of the thioimidazolium scaffold.
T101 (L-682.777) is a good blocker of tissue transglutaminase and coagulation factor XIIIa. Both enzymes are inhibited with an IC50 of about 0.25 μM.
D004 (L-683.685) is a good blocker of tissue transglutaminase and coagulation factor XIIIa. Both enzymes are blocked with an IC50 of about 0.35 μM.
D003 is a weak blocker of tissue transglutaminase with an IC50 of about 1.0 μM.