International Journal of Molecular Sciences · 4 authors, 2 centres
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This in vitro and ex vivo study tested two inhibitors of transglutaminase 2 (TG2), PX-12 and ERW1041, for their ability to block gliadin peptide transport and enzyme activity in intestinal cells and celiac patient biopsies. The irreversible inhibitor ERW1041 was effective in inhibiting TG2 activity and the transport of the immunogenic gliadin peptide P56-88, while the oxidative inhibitor PX-12 was ineffective in cellular assays, possibly due to rapid degradation.
Celiac disease is an autoimmune disorder with no non-dietary treatments; inhibiting transglutaminase 2 (TG2) is a potential therapeutic target. This preclinical study investigated the effects of two TG2 inhibitors, PX-12 and ERW1041, using purified enzyme, the Caco-2 intestinal epithelial cell line, and ex vivo duodenal biopsies from celiac disease patients. The key finding was that the irreversible inhibitor ERW1041 significantly reduced TG2 activity in all tested systems and inhibited the transepithelial transport of the immunogenic gliadin peptide P56-88 across Caco-2 cell monolayers. In contrast, the oxidative inhibitor PX-12 was more potent on purified enzyme but failed to inhibit TG2 activity or peptide transport in cellular assays, likely due to rapid cellular inactivation or degradation. The study also confirmed that the transport of peptide P31-43 is not dependent on TG2. Limitations include the in vitro and ex vivo nature of the work, which does not assess effects on downstream inflammation or clinical outcomes, and the potential discrepancy between cell line models and in vivo human physiology. The results suggest that potent, stable TG2 inhibitors like ERW1041 could potentially prevent the initial step of gliadin peptide translocation across the gut epithelium, representing a plausible non-dietary intervention for celiac disease, though further research is needed to evaluate efficacy against gliadin-induced inflammation.
