Oral and Inhaled Fosamprenavir Reverses Pepsin-Induced Damage in a Laryngopharyngeal Reflux Mouse Model. Laryngoscope 2023 Jan;133 Suppl 1(Suppl 1):S1-S11
Date
06/10/2022Pubmed ID
35678265Pubmed Central ID
PMC9732152DOI
10.1002/lary.30242Scopus ID
2-s2.0-85131512635 (requires institutional sign-in at Scopus site) 6 CitationsAbstract
OBJECTIVE: 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-mediated laryngeal damage in vivo.
METHODS: Drug and pepsin binding and inhibition were screened by high-throughput assays and crystallography. A mouse model of laryngopharyngeal reflux (mechanical laryngeal injury once weekly for 2 weeks and pH 7 solvent/pepsin instillation 3 days/week for 4 weeks) was provided inhibitor by gavage or aerosol (fosamprenavir or darunavir; 5 days/week for 4 weeks; n = 3). Larynges were collected for histopathologic analysis.
RESULTS: HIV protease inhibitors amprenavir, ritonavir, saquinavir, and darunavir bound and inhibited pepsin with IC50 in the low micromolar range. Gavage and aerosol fosamprenavir prevented pepsin-mediated 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.
CONCLUSIONS: Fosamprenavir and darunavir, FDA-approved therapies for HIV/AIDS, bind and inhibit pepsin, abrogating pepsin-mediated 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.
LEVEL OF EVIDENCE: NA. Laryngoscope, 133:S1-S11, 2023.
Author List
Johnston N, Samuels TL, Goetz CJ, Arnold LA, Smith BC, Seabloom D, Wuertz B, Ondrey F, Wiedmann TS, Vuksanovic N, Silvaggi NR, MacKinnon AC, Miller J, Bock J, Blumin JHAuthors
Alexander (Leggy) Arnold PhD Professor in the Chemistry & Biochemistry department at University of Wisconsin - MilwaukeeJoel H. Blumin MD Chief, Professor in the Otolaryngology department at Medical College of Wisconsin
Jonathan Bock MD Professor in the Otolaryngology department at Medical College of Wisconsin
Nikki Johnston PhD Professor in the Otolaryngology department at Medical College of Wisconsin
James Adam Miller MD, MPH Assistant Professor in the Pathology department at Medical College of Wisconsin
Brian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsCarbamates
Furans
Laryngopharyngeal Reflux
Larynx
Mice
Pepsin A
Sulfonamides