Inhibition of dysregulated tissue transglutaminase (tTG, TG2)
Celiac disease is the most common chronic inflammation of the small intestine affecting more than 1% of the Western population. For decades it has been known that the external trigger is gluten (a cereal protein) inducing the inflammation in genetically susceptible people. Gluten – or more precisely the gliadin peptides derived by digestion – fits perfectly to the active site of tissue transglutaminase. In the small intestinal mucosa, gliadin peptides are enzymatically modified by tissue transglutaminase (also known as TG2).
This modification, a deamidation in a chemical sense, results in the introduction of a negative charge into the gliadin molecule by transforming glutamine to glutamic acid. Subsequently the deamidated gliadin is recognized by the immune cells triggering and amplifying the inflammation process. The vicious circle consisting of inflammation, transglutaminase secretion and activation, deamidation of gliadin and further stimulation of the immune response destroys the villi responsible for absorption of nutrition.
Zedira’s therapeutic approach is intercepting the vicious circle by blocking dysregulated tissue transglutaminase. To achieve this, we developed drug candidate ZED-101, a small molecule representing a novel class of transglutaminase inhibitors. ZED1227 is a peptidomimetic compound obtained by rational drug design. ZED1227 combines high potency and selectivity for the target tissue transglutaminase.
ZED1227 has been licensed to Dr. Falk Pharma (Freiburg, Germany) for preclinical and clinical development, approval and marketing in Europe.
Until a drug is approved by the authorities, a strict gluten free diet (cumbersome but efficient) is the only way for patients and their families to handle celiac disease. In addition to physicians, national patients’ organizations provide excellent support for managing the disease.