{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T16:46:14Z","timestamp":1785775574338,"version":"3.56.0"},"reference-count":96,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,4,5]],"date-time":"2023-04-05T00:00:00Z","timestamp":1680652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical College of Wisconsin Department of Otolaryngology and Communication Sciences"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Gastroesophageal reflux disease (GERD) significantly impacts patient quality of life and is a major risk factor for the development of Barrett\u2019s esophagus (BE) and esophageal adenocarcinoma (EAC). Proton pump inhibitors (PPIs) are the standard-of-care for GERD and are among the most prescribed drugs in the world, but do not protect against nonacid components of reflux such as pepsin, or prevent reflux-associated carcinogenesis. We recently identified an HIV protease inhibitor amprenavir that inhibits pepsin and demonstrated the antireflux therapeutic potential of its prodrug fosamprenavir in a mouse model of laryngopharyngeal reflux. In this study, we assessed the capacity of amprenavir to protect against esophageal epithelial barrier disruption in vitro and related molecular events, E-cadherin cleavage, and matrix metalloproteinase induction, which are associated with GERD severity and esophageal cancer. Herein, weakly acidified pepsin (though not acid alone) caused cell dissociation accompanied by regulated intramembrane proteolysis of E-cadherin. Soluble E-cadherin responsive matrix metalloproteinases (MMPs) were transcriptionally upregulated 24 h post-treatment. Amprenavir, at serum concentrations achievable given the manufacturer-recommended dose of fosamprenavir, protected against pepsin-induced cell dissociation, E-cadherin cleavage, and MMP induction. These results support a potential therapeutic role for amprenavir in GERD recalcitrant to PPI therapy and for preventing GERD-associated neoplastic changes.<\/jats:p>","DOI":"10.3390\/ijms24076765","type":"journal-article","created":{"date-parts":[[2023,4,5]],"date-time":"2023-04-05T02:11:41Z","timestamp":1680660701000},"page":"6765","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["The Protease Inhibitor Amprenavir Protects against Pepsin-Induced Esophageal Epithelial Barrier Disruption and Cancer-Associated Changes"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6027-1409","authenticated-orcid":false,"given":"Simon","family":"Blaine-Sauer","sequence":"first","affiliation":[{"name":"Department of Otolaryngology and Communication Science, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7045-357X","authenticated-orcid":false,"given":"Tina L.","family":"Samuels","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology and Communication Science, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Quantitative Health Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikki","family":"Johnston","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology and Communication Science, Medical College of Wisconsin, Milwaukee, WI 53226, USA"},{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2536","DOI":"10.1001\/jama.2020.21360","article-title":"Gastroesophageal Reflux Disease: A Review","volume":"324","author":"Markar","year":"2020","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1136\/gutjnl-2016-313589","article-title":"Global Prevalence of, and Risk Factors for, Gastro-Oesophageal Reflux Symptoms: A Meta-Analysis","volume":"67","author":"Eusebi","year":"2018","journal-title":"Gut"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1053\/j.gastro.2017.07.045","article-title":"Presentation and Epidemiology of Gastroesophageal Reflux Disease","volume":"154","author":"Richter","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.giec.2019.12.004","article-title":"Laryngopharyngeal Reflux and Atypical Gastroesophageal Reflux Disease","volume":"30","author":"Barrett","year":"2020","journal-title":"Gastrointest. 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