Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease
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-med...
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MDPI AG
2022-05-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/10/1667 |
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| author | Christian Büchold Martin Hils Uwe Gerlach Johannes Weber Christiane Pelzer Andreas Heil Daniel Aeschlimann Ralf Pasternack |
| author_facet | Christian Büchold Martin Hils Uwe Gerlach Johannes Weber Christiane Pelzer Andreas Heil Daniel Aeschlimann Ralf Pasternack |
| author_sort | Christian Büchold |
| collection | DOAJ |
| description | 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 Ca<sup>2+</sup>, 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. |
| first_indexed | 2024-03-10T03:09:58Z |
| format | Article |
| id | doaj.art-b70e5471a4a248129807f527f0910cf4 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T03:09:58Z |
| publishDate | 2022-05-01 |
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| series | Cells |
| spelling | doaj.art-b70e5471a4a248129807f527f0910cf42023-11-23T10:27:56ZengMDPI AGCells2073-44092022-05-011110166710.3390/cells11101667Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac DiseaseChristian Büchold0Martin Hils1Uwe Gerlach2Johannes Weber3Christiane Pelzer4Andreas Heil5Daniel Aeschlimann6Ralf Pasternack7Zedira GmbH, Roesslerstrasse 83, 64293 Darmstadt, GermanyZedira GmbH, Roesslerstrasse 83, 64293 Darmstadt, GermanySanofi-Aventis Deutschland GmbH, UG Serves as External Consultant for Medicinal Chemistry to Zedira, 65926 Frankfurt, GermanyZedira GmbH, Roesslerstrasse 83, 64293 Darmstadt, GermanyZedira GmbH, Roesslerstrasse 83, 64293 Darmstadt, GermanyZedira GmbH, Roesslerstrasse 83, 64293 Darmstadt, GermanyMatrix Biology & Tissue Repair Research Unit, School of Dentistry, Cardiff University, Heath Park, Cardiff CF14 4XY, Wales, UKZedira GmbH, Roesslerstrasse 83, 64293 Darmstadt, GermanyZED1227 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 Ca<sup>2+</sup>, 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.https://www.mdpi.com/2073-4409/11/10/1667tissue transglutaminasetransglutaminase inhibitorceliac diseasedrug discovery |
| spellingShingle | Christian Büchold Martin Hils Uwe Gerlach Johannes Weber Christiane Pelzer Andreas Heil Daniel Aeschlimann Ralf Pasternack Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease Cells tissue transglutaminase transglutaminase inhibitor celiac disease drug discovery |
| title | Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease |
| title_full | Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease |
| title_fullStr | Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease |
| title_full_unstemmed | Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease |
| title_short | Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease |
| title_sort | features of zed1227 the first in class tissue transglutaminase inhibitor undergoing clinical evaluation for the treatment of celiac disease |
| topic | tissue transglutaminase transglutaminase inhibitor celiac disease drug discovery |
| url | https://www.mdpi.com/2073-4409/11/10/1667 |
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