{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T16:52:40Z","timestamp":1786553560104,"version":"build-2736575974"},"reference-count":140,"publisher":"Wiley","issue":"S1","license":[{"start":{"date-parts":[[2022,6,9]],"date-time":"2022-06-09T00:00:00Z","timestamp":1654732800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM128840"],"award-info":[{"award-number":["R35GM128840"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Laryngoscope"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>More than 20% of the US population suffers from laryngopharyngeal reflux. Although dietary\/lifestyle modifications and alginates provide benefit to some, there is no gold standard medical therapy. Increasing evidence suggests that pepsin is partly, if not wholly, responsible for damage and inflammation caused by laryngopharyngeal reflux. A treatment specifically targeting pepsin would be amenable to local, inhaled delivery, and could prove effective for endoscopic signs and symptoms associated with nonacid reflux. The aim herein was to identify small molecule inhibitors of pepsin and test their efficacy to prevent pepsin\u2010mediated laryngeal damage in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Drug and pepsin binding and inhibition were screened by high\u2010throughput assays and crystallography. A mouse model of laryngopharyngeal reflux (mechanical laryngeal injury once weekly for 2\u2009weeks and pH\u20097 solvent\/pepsin instillation 3\u2009days\/week for 4\u2009weeks) was provided inhibitor by gavage or aerosol (fosamprenavir or darunavir; 5\u2009days\/week for 4\u2009weeks; <jats:italic>n<\/jats:italic>\u00a0=\u00a03). Larynges were collected for histopathologic analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>HIV protease inhibitors amprenavir, ritonavir, saquinavir, and darunavir bound and inhibited pepsin with IC<jats:sub>50<\/jats:sub> in the low micromolar range. Gavage and aerosol fosamprenavir prevented pepsin\u2010mediated laryngeal damage (i.e., reactive epithelia, increased intraepithelial inflammatory cells, and cell apoptosis). Darunavir gavage elicited mild reactivity and no discernable protection; aerosol protected against apoptosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Fosamprenavir and darunavir, FDA\u2010approved therapies for HIV\/AIDS, bind and inhibit pepsin, abrogating pepsin\u2010mediated laryngeal damage in a laryngopharyngeal reflux mouse model. These drugs target a foreign virus, making them ideal to repurpose. Reformulation for local inhaled delivery could further improve outcomes and limit side effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Level of evidence<\/jats:title><jats:p>NA. <jats:italic>Laryngoscope<\/jats:italic>, 133:S1\u2013S11, 2023<\/jats:p><\/jats:sec>","DOI":"10.1002\/lary.30242","type":"journal-article","created":{"date-parts":[[2022,6,9]],"date-time":"2022-06-09T10:13:10Z","timestamp":1654769590000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Oral and Inhaled Fosamprenavir Reverses Pepsin\u2010Induced Damage in a Laryngopharyngeal Reflux Mouse Model"],"prefix":"10.1002","volume":"133","author":[{"given":"Nikki","family":"Johnston","sequence":"first","affiliation":[{"name":"Department of Otolaryngology and Communication Science Medical College of Wisconsin  Milwaukee Wisconsin U.S.A."},{"name":"Department of Microbiology and Immunology Medical College of Wisconsin  Milwaukee Wisconsin 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Biochemistry Medical College of Wisconsin  Milwaukee Wisconsin U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna","family":"Seabloom","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery University of Minnesota  Minneapolis Minnesota U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beverly","family":"Wuertz","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery University of Minnesota  Minneapolis Minnesota U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4951-9335","authenticated-orcid":false,"given":"Frank","family":"Ondrey","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery University of Minnesota  Minneapolis Minnesota U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy 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