2. Academic Validation
  3. Oral and Inhaled Fosamprenavir Reverses Pepsin-Induced Damage in a Laryngopharyngeal Reflux Mouse Model

Oral and Inhaled Fosamprenavir Reverses Pepsin-Induced Damage in a Laryngopharyngeal Reflux Mouse Model

  • Laryngoscope. 2023 Jan;133 Suppl 1(Suppl 1):S1-S11. doi: 10.1002/lary.30242.
Nikki Johnston 1 2,  Tina L Samuels 1,  Christopher J Goetz 3,  Leggy A Arnold 4,  Brian C Smith 3,  Donna Seabloom 5,  Beverly Wuertz 5,  Frank Ondrey 5,  Timothy S Wiedmann 6,  Nemanja Vuksanovic 4,  Nicholas R Silvaggi 4,  Alexander C MacKinnon 7,  James Miller 8,  Jonathan Bock 1,  Joel H Blumin 1
Affiliations

Affiliations

  • 1 Department of Otolaryngology and Communication Science, Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A.
  • 2 Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A.
  • 3 Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A.
  • 4 Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin, Milwaukee, Wisconsin, U.S.A.
  • 5 Department of Otolaryngology Head and Neck Surgery, University of Minnesota, Minneapolis, Minnesota, U.S.A.
  • 6 Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota, U.S.A.
  • 7 Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, U.S.A.
  • 8 Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A.
PMID: 35678265 DOI: 10.1002/lary.30242
Abstract

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.

Keywords

LPR; Laryngopharyngeal reflux; darunavir; fosamprenavir; pepsin.

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