Su1161 - The Oral Transglutaminase 2 (TG2) Inhibitor Zed1227 Blocks TG2 Activity in a Mouse Model of Intestinal Inflammation

Ventura, Manuel A. Encalada; Sajko, Kaja; Hils, Martin; Pasternack, Ralf; Greinwald, Roland; Tewes, Bernhard; Schuppan, Detlef

doi:10.1016/s0016-5085(18)31861-4

Cited by 14 publications

(8 citation statements)

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“…The oral administration of the dihydroisoxazole inhibitor ERW1041E reduced TG2 activation, thus counteracting intestinal inflammation. Similar results were also obtained using a DON compound of the new generation, ZED1227 [ 119 , 120 ]. Furthermore, in a transgenic mouse model overexpressing IL15 at the intestinal level and expressing DQ8 molecules, a gluten-containing diet caused mucosal atrophy, increased TG2 expression and activity and humoral response against gliadin, and deamidated gliadin peptides [ 121 ].…”

Section: Tg2 In CD Therapysupporting

confidence: 74%

Type 2 Transglutaminase in Coeliac Disease: A Key Player in Pathogenesis, Diagnosis and Therapy

Paolella

Sposito

Romanelli

et al. 2022

IJMS

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Type 2 transglutaminase (TG2) is the main autoantigen in coeliac disease (CD), a widespread inflammatory enteropathy caused by the ingestion of gluten-containing cereals in genetically predisposed individuals. As a consequence, serum antibodies to TG2 represent a very useful marker in CD diagnosis. However, TG2 is also an important player in CD pathogenesis, for its ability to deamidate some Gln residues of gluten peptides, which become more immunogenic in CD intestinal mucosa. Given the importance of TG2 enzymatic activities in CD, several studies have sought to discover specific and potent inhibitors that could be employed in new therapeutical approaches for CD, as alternatives to a lifelong gluten-free diet. In this review, we summarise all the aspects regarding TG2 involvement in CD, including its enzymatic reactions in pathogenesis, the role of anti-TG2 antibodies in disease management, and the exploration of recent strategies to reduce deamidation or to use transamidation to detoxify gluten.

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Section: Tg2 In CD Therapysupporting

confidence: 74%

Type 2 Transglutaminase in Coeliac Disease: A Key Player in Pathogenesis, Diagnosis and Therapy

Paolella

Sposito

Romanelli

et al. 2022

IJMS

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“…Other strategies involve modulation of tight junctions by targeting zonulins (198)(199)(200); blocking of IL-15 using anti-IL monoclonal antibodies (138,(201)(202)(203), blocking HLADQ2 or HLADQ8 by HLA blockers (138), use of geneticallymodified gluten with modified glutamine residues (192), use of transglutaminase inhibitors (192,(195)(196)(197) and use of tolerogenic nanoparticles (204)(205)(206). Use of anti-inflammatory drugs (186,187), anti-IFN-γ, anti-TNF-α (188)(189)(190), and anti-IL-15 agents (175) have also been suggested in reducing CD toxicity.…”

Section: Strategies For Lowering Down CD Epitopesmentioning

confidence: 99%

Pathogenesis of Celiac Disease and Other Gluten Related Disorders in Wheat and Strategies for Mitigating Them

et al. 2020

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Wheat is a major cereal crop providing energy and nutrients to the billions of people around the world. Gluten is a structural protein in wheat, that is necessary for its dough making properties, but it is responsible for imparting certain intolerances among some individuals, which are part of this review. Most important among these intolerances is celiac disease, that is gluten triggered T-cell mediated autoimmune enteropathy and results in villous atrophy, inflammation and damage to intestinal lining in genetically liable individuals containing human leukocyte antigen DQ2/DQ8 molecules on antigen presenting cells. Celiac disease occurs due to presence of celiac disease eliciting epitopes in gluten, particularly highly immunogenic alpha-gliadins. Another gluten related disorder is non-celiac gluten-sensitivity in which innate immune-response occurs in patients along with gastrointestinal and non-gastrointestinal symptoms, that disappear upon removal of gluten from the diet. In wheat allergy, either IgE or non-IgE mediated immune response occurs in individuals after inhalation or ingestion of wheat. Following a lifelong gluten-free diet by celiac disease and non-celiac gluten-sensitivity patients is very challenging as none of wheat cultivar or related species stands safe for consumption. Hence, different molecular biology, genetic engineering, breeding, microbial, enzymatic, and chemical strategies have been worked upon to reduce the celiac disease epitopes and the gluten content in wheat. Currently, only 8.4% of total population is affected by wheat-related issues, while rest of population remains safe and should not remove wheat from the diet, based on false media coverage.

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“…A similar approach has been taken with the pharmaceutical therapy Zedira, or ZED1227, which irreversibly blocks TG2. In a mouse model of intestinal inflammation, ZED1227 has been shown to reduce TG2 activity between 2- and 4-fold after intraperitoneal injection [ 99 ]. This therapy has been investigated for safety and tolerability in Phase 1 clinical trials and has recently advanced to Phase 2 trials for efficacy in celiac disease treatment [ 100 , 101 ].…”

Section: Current Treatment Strategies Undergoing Clinical Trialmentioning

confidence: 99%

Gliadin Sequestration as a Novel Therapy for Celiac Disease: A Prospective Application for Polyphenols

Buiten

Elias

2021

IJMS

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Celiac disease is an autoimmune disorder characterized by a heightened immune response to gluten proteins in the diet, leading to gastrointestinal symptoms and mucosal damage localized to the small intestine. Despite its prevalence, the only treatment currently available for celiac disease is complete avoidance of gluten proteins in the diet. Ongoing clinical trials have focused on targeting the immune response or gluten proteins through methods such as immunosuppression, enhanced protein degradation and protein sequestration. Recent studies suggest that polyphenols may elicit protective effects within the celiac disease milieu by disrupting the enzymatic hydrolysis of gluten proteins, sequestering gluten proteins from recognition by critical receptors in pathogenesis and exerting anti-inflammatory effects on the system as a whole. This review highlights mechanisms by which polyphenols can protect against celiac disease, takes a critical look at recent works and outlines future applications for this potential treatment method.

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Su1161 - The Oral Transglutaminase 2 (TG2) Inhibitor Zed1227 Blocks TG2 Activity in a Mouse Model of Intestinal Inflammation

Cited by 14 publications

References 0 publications

Type 2 Transglutaminase in Coeliac Disease: A Key Player in Pathogenesis, Diagnosis and Therapy

Type 2 Transglutaminase in Coeliac Disease: A Key Player in Pathogenesis, Diagnosis and Therapy

Pathogenesis of Celiac Disease and Other Gluten Related Disorders in Wheat and Strategies for Mitigating Them

Gliadin Sequestration as a Novel Therapy for Celiac Disease: A Prospective Application for Polyphenols

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