{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T05:06:44Z","timestamp":1791090404390,"version":"4.1.0"},"reference-count":45,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T00:00:00Z","timestamp":1614816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","award":["AS262Z01275Q"],"award-info":[{"award-number":["AS262Z01275Q"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","award":["AS242Z00566Q"],"award-info":[{"award-number":["AS242Z00566Q"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["15H04337"],"award-info":[{"award-number":["15H04337"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["TS-PRINT 20lm0203011-j0002"],"award-info":[{"award-number":["TS-PRINT 20lm0203011-j0002"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Bioavailability is a major bottleneck in the clinical application of medium molecular weight therapeutics, including protein and peptide drugs. Paracellular transport of these molecules is hampered by intercellular tight junction (TJ) complexes. Therefore, safe chemical regulators for TJ loosening are desired. Here, we showed a potential application of select non-steroidal anti-inflammatory drugs (NSAIDs) as TJ modulators. Based on our previous observation that diclofenac and flufenamic acid directly bound various PDZ domains with a broad specificity, we applied solution nuclear magnetic resonance techniques to examine the interaction of other NSAIDs and the first PDZ domain (PDZ1) of zonula occludens (ZO)-1, ZO-1(PDZ1). Inhibition of ZO-1(PDZ1) is expected to provide loosening of the epithelial barrier function because the domain plays a crucial role in maintaining TJ integrity. Accordingly, diclofenac and indomethacin were found to decrease the subcellular localization of claudin (CLD)-2 but not occludin and ZO-1 at the apicolateral intercellular compartment of Madin\u2013Darby canine kidney (MDCK) II cells. These NSAIDs exhibited 125\u2013155% improved paracellular efflux of fluorescein isothiocyanate insulin for the Caco-2 cell monolayer. We propose that these NSAIDs can be repurposed as drug absorption enhancers for peptide drugs.<\/jats:p>","DOI":"10.3390\/ijms22052583","type":"journal-article","created":{"date-parts":[[2021,3,5]],"date-time":"2021-03-05T00:39:07Z","timestamp":1614904747000},"page":"2583","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["NMR-Guided Repositioning of Non-Steroidal Anti-Inflammatory Drugs into Tight Junction Modulators"],"prefix":"10.3390","volume":"22","author":[{"given":"Takeshi","family":"Tenno","sequence":"first","affiliation":[{"name":"Laboratory of Structural and Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya 464-8601, Aichi, Japan"},{"name":"BeCellBar, LLC, Nagoya 464-8601, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohki","family":"Kataoka","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science, Nagoya University, Nagoya 464-8602, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natsuko","family":"Goda","sequence":"additional","affiliation":[{"name":"Laboratory of Structural and Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya 464-8601, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1621-5893","authenticated-orcid":false,"given":"Hidekazu","family":"Hiroaki","sequence":"additional","affiliation":[{"name":"Laboratory of Structural and Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya 464-8601, Aichi, Japan"},{"name":"BeCellBar, LLC, Nagoya 464-8601, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.drudis.2014.10.003","article-title":"Peptide therapeutics: Current status and future directions","volume":"20","author":"Fosgerau","year":"2015","journal-title":"Drug Discov. 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