Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease

Cells

Daniel Aeschlimann¹  Uwe Gerlach²  Johannes Weber³  Christian Büchold³  Martin Hils³  Ralf Pasternack³  Christiane Pelzer³  Andreas Heil³ 

[1] Matrix Biology & Tissue Repair Research Unit, School of Dentistry, Cardiff University, Heath Park, Cardiff CF14 4XY, Wales, UK;Sanofi-Aventis Deutschland GmbH, UG Serves as External Consultant for Medicinal Chemistry to Zedira, 65926 Frankfurt, Germany;Zedira GmbH, Roesslerstrasse 83, 64293 Darmstadt, Germany;

关键词: tissue transglutaminase;    transglutaminase inhibitor;    celiac disease;    drug discovery;   

DOI  :  10.3390/cells11101667

来源: DOAJ

【 摘 要 】

ZED1227 is a small molecule tissue transglutaminase (TG2) inhibitor. The compound selectively binds to the active state of TG2, forming a stable covalent bond with the cysteine in its catalytic center. The molecule was designed for the treatment of celiac disease. Celiac disease is an autoimmune-mediated chronic inflammatory condition of the small intestine affecting about 1–2% of people in Caucasian populations. The autoimmune disease is triggered by dietary gluten. Consumption of staple foods containing wheat, barley, or rye leads to destruction of the small intestinal mucosa in genetically susceptible individuals, and this is accompanied by the generation of characteristic TG2 autoantibodies. TG2 plays a causative role in the pathogenesis of celiac disease. Upon activation by Ca²⁺, it catalyzes the deamidation of gliadin peptides as well as the crosslinking of gliadin peptides to TG2 itself. These modified biological structures trigger breaking of oral tolerance to gluten, self-tolerance to TG2, and the activation of cytotoxic immune cells in the gut mucosa. Recently, in an exploratory proof-of-concept study, ZED1227 administration clinically validated TG2 as a “druggable” target in celiac disease. Here, we describe the specific features and profiling data of the drug candidate ZED1227. Further, we give an outlook on TG2 inhibition as a therapeutic approach in indications beyond celiac disease.

【 授权许可】

Unknown