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ORIGINAL RESEARCH article
Front. Immunol.
Sec. Nutritional Immunology
Volume 15 - 2024 |
doi: 10.3389/fimmu.2024.1425982
This article is part of the Research Topic Gluten-Related Disorders: Pathogenesis, Diagnosis, and Treatment View all 7 articles
Exopeptidase combination enhances the rapid degradation of isotopically labelled gluten immunogenic peptides in humans
Provisionally accepted- 1 AMYRA Biotech AG, Basel, Switzerland
- 2 Center of Drug Absorption and Transport, University Medicine Greifswald, Greifswald, Mecklenburg-Vorpommern, Germany
Introduction. Celiac disease is a common autoimmune-like enteropathy caused by an aberrant response to incompletely digested dietary gluten. Gluten immunogenic peptides including the immunodominant 33-mer are thought to be resistant to proteolytic digestion by human gastrointestinal peptidases. We developed a novel enzyme therapy approach to support gluten peptide digestion using a combination of two tandem-acting exopeptidases, AMYNOPEP, that complement the intrinsic enzymatic activity of intestinal brush border enterocytes. Methods. We evaluated the effects of AMYNOPEP supplementation on 33-mer degradation in vitro and in vivo. In a cross-over clinical study, healthy volunteers with no gastrointestinal disorders were given stable isotope (SI) labelled 33-mer peptides in the presence of varying peptide substrates and caloric loads, with and without AMYNOPEP. 33-mer degradation products (SI-labelled single amino acids) were measured in the blood plasma using LC-MS/MS. Results. AMYNOPEP achieved rapid, complete amino-to-carboxyl terminal degradation of the 33-mer in vitro, generating single amino acids and dipeptides. In healthy volunteers, AMYNOPEP supplementation significantly increased 33-mer degradation and absorption of SI-labelled amino acids even in the presence of competing substrates. Specifically, we observed a 2.8-fold increase in the Cmax of stable isotope-labelled amino acids in the presence of wheat gluten. The absorption kinetics of labelled amino acids derived from 33-mer digestion with AMYNOPEP closely resembled that of SI-labelled X-Proline dipeptides administered without enzyme supplementation, highlighting the rapid hydrolytic activity of AMYNOPEP on polypeptides. Conclusions. AMYNOPEP achieved complete degradation of the 33-mer into single amino acids and dipeptides in vitro and significantly improved 33-mer degradation kinetics in healthy volunteers, as measured by labelled amino acid detection, warranting further investigation into the potential therapeutic benefits of exopeptidase combinations for patients with gluten-related health disorders including celiac disease.
Keywords: Celiac, Exopeptidase, Glutenase, Enzyme therapeutics, gluten
Received: 30 Apr 2024; Accepted: 16 Sep 2024.
Copyright: © 2024 Mourabit, Römer, Bonner, Winter, Tschollar, Tzvetkov, Weitschies, Engeli and Tschollar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Sulayman Mourabit, AMYRA Biotech AG, Basel, Switzerland
Fabian Winter, Center of Drug Absorption and Transport, University Medicine Greifswald, Greifswald, Mecklenburg-Vorpommern, Germany
Julian Tschollar, AMYRA Biotech AG, Basel, Switzerland
Stefan Engeli, Center of Drug Absorption and Transport, University Medicine Greifswald, Greifswald, Mecklenburg-Vorpommern, Germany
Werner Tschollar, AMYRA Biotech AG, Basel, Switzerland
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