{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:57:12Z","timestamp":1790625432150,"version":"4.1.0"},"reference-count":16,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T00:00:00Z","timestamp":1687910400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital","award":["9AC098"],"award-info":[{"award-number":["9AC098"]}]},{"name":"The Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital","award":["9V041"],"award-info":[{"award-number":["9V041"]}]},{"name":"The Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital","award":["9X035"],"award-info":[{"award-number":["9X035"]}]},{"name":"The Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital","award":["9AA053"],"award-info":[{"award-number":["9AA053"]}]},{"name":"Dr. Falk Pharma","award":["9AC098"],"award-info":[{"award-number":["9AC098"]}]},{"name":"Dr. Falk Pharma","award":["9V041"],"award-info":[{"award-number":["9V041"]}]},{"name":"Dr. Falk Pharma","award":["9X035"],"award-info":[{"award-number":["9X035"]}]},{"name":"Dr. Falk Pharma","award":["9AA053"],"award-info":[{"award-number":["9AA053"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The enzyme transglutaminase 2 (TG2) plays a key role in celiac disease (CeD) pathogenesis. Active TG2 is located mainly extracellularly in the lamina propria but also in the villous enterocytes of the duodenum. The TG2 inhibitor ZED1227 is a promising drug candidate for treating CeD and is designed to block the TG2-catalyzed deamidation and crosslinking of gliadin peptides. Our aim was to study the accumulation of ZED1227 after oral administration of the drug. We studied duodenal biopsies derived from a phase 2a clinical drug trial using an antibody that detects ZED1227 when bound to the catalytic center of TG2. Human epithelial organoids were studied in vitro for the effect of ZED1227 on the activity of TG2 using the 5-biotin-pentylamine assay. The ZED1227-TG2 complex was found mainly in the villous enterocytes in post-treatment biopsies. The signal of ZED1227-TG2 was strongest in the luminal epithelial brush border, while the intensity of the signal in the lamina propria was only ~20% of that in the villous enterocytes. No signal specific to ZED1227 could be detected in pretreatment biopsies or in biopsies from patients randomized to the placebo treatment arm. ZED1227-TG2 staining co-localized with total TG2 and native and deamidated gliadin peptides on the enterocyte luminal surface. Inhibition of TG2 activity by ZED1227 was demonstrated in epithelial organoids. Our findings suggest that active TG2 is present at the luminal side of the villous epithelium and that inhibition of TG2 activity by ZED1227 occurs already there before gliadin peptides enter the lamina propria.<\/jats:p>","DOI":"10.3390\/ijms241310815","type":"journal-article","created":{"date-parts":[[2023,6,29]],"date-time":"2023-06-29T00:41:45Z","timestamp":1687999305000},"page":"10815","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["The Oral Transglutaminase 2 Inhibitor ZED1227 Accumulates in the Villous Enterocytes in Celiac Disease Patients during Gluten Challenge and Drug Treatment"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0849-5939","authenticated-orcid":false,"given":"Jorma","family":"Isola","sequence":"first","affiliation":[{"name":"Jilab Inc., 33520 Tampere, Finland"},{"name":"Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markku","family":"M\u00e4ki","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5400-3600","authenticated-orcid":false,"given":"Martin","family":"Hils","sequence":"additional","affiliation":[{"name":"Zedira GmbH, Roesslerstrasse 83, 64293 Darmstadt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Pasternack","sequence":"additional","affiliation":[{"name":"Zedira GmbH, Roesslerstrasse 83, 64293 Darmstadt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7167-5094","authenticated-orcid":false,"given":"Keijo","family":"Viiri","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeriia","family":"Dotsenko","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toni","family":"Montonen","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Dr. Falk Pharma Gmbh, 79108 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Mohrbacher","sequence":"additional","affiliation":[{"name":"Dr. Falk Pharma Gmbh, 79108 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Greinwald","sequence":"additional","affiliation":[{"name":"Dr. Falk Pharma Gmbh, 79108 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Detlef","family":"Schuppan","sequence":"additional","affiliation":[{"name":"Institute of Translational Immunology and Celiac Center, Medical Center, Johannes-Gutenberg University, 55099 Mainz, Germany"},{"name":"Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41575-020-00378-1","article-title":"Current and emerging therapies for coeliac disease","volume":"18","author":"Caminero","year":"2021","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1136\/gut.2003.024836","article-title":"In vivo targeting of intestinal and extraintestinal transglutaminase 2 by coeliac autoantibodies","volume":"53","author":"Halttunen","year":"2004","journal-title":"Gut"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"9","DOI":"10.3389\/fmed.2014.00009","article-title":"Beyond the Intestinal Celiac Mucosa: Diagnostic Role of Anti-TG2 Deposits, a Systematic Review","volume":"1","author":"Gatti","year":"2014","journal-title":"Front. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1053\/j.gastro.2020.04.018","article-title":"Evidence That Pathogenic Transglutaminase 2 in Celiac Disease Derives from Enterocytes","volume":"159","author":"Iversen","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1038\/s41586-021-03852-1","article-title":"Cells of the human intestinal tract mapped across space and time","volume":"597","author":"Elmentaite","year":"2021","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1053\/j.gastro.2005.07.054","article-title":"Unexpected Role of Surface Transglutaminase Type II in Celiac Disease","volume":"129","author":"Maiuri","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1007\/s00441-014-1990-x","article-title":"Characterization of distinct sub-cellular location of transglutaminase type II: Changes in intracellular distribution in physiological and pathological states","volume":"358","author":"Piacentini","year":"2014","journal-title":"Cell Tissue Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Siegel, M., Strnad, P., Watts, R.E., Choi, K., Jabri, B., Omary, M.B., and Khosla, C. (2008). Extracellular transglutaminase 2 is catalytically inactive, but is transiently activated upon tissue injury. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0001861"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"113560","DOI":"10.1016\/j.ab.2019.113560","article-title":"Substrates, inhibitors, and probes of mammalian transglutaminase 2","volume":"15","author":"Zhuang","year":"2020","journal-title":"Anal. Biochem."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"B\u00fcchold, C., Hils, M., Gerlach, U., Weber, J., Pelzer, C., Heil, A., Aeschlimann, D., and Pasternack, R. (2022). Features of ZED1227: The first-in-class tissue transglutaminase inhibitor undergoing clinical evaluation for the treatment of celiac disease. Cells, 11.","DOI":"10.3390\/cells11101667"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1056\/NEJMoa2032441","article-title":"CEC-3 Trial Group. A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease","volume":"385","author":"Schuppan","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_12","unstructured":"Dotsenko, V., Sioofy-Khojine, A.B., Hy\u00f6ty, H., and Viiri, K. (2023). Methods in Cell Biology, Academic Press."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time, P.C.R data by the comparative, C.T. method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1038\/nri885","article-title":"Coeliac disease: Dissecting a complex inflammatory disorder","volume":"2","author":"Sollid","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Taavela, J., Viiri, K., Popp, A., Oittinen, M., Dotsenko, V., Per\u00e4aho, M., Staff, S., Sarin, J., Leon, F., and M\u00e4ki, M. (2019). Histological, immunohistochemical and mRNA gene expression responses in coeliac disease patients challenged with gluten using, P.A.Xgene fixed paraffin-embedded duodenal biopsies. BMC Gastroenterol., 19.","DOI":"10.1186\/s12876-019-1089-7"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. 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