Topical TMPRSS2 inhibition prevents SARS-CoV-2 infection in differentiated human airway cultures

• Published in: Life science alliance Vol. 5; no. 4; p. e202101116
• Main Authors: Guo, Wenrui, Porter, Linsey M, Crozier, Thomas WM, Coates, Matthew, Jha, Akhilesh, McKie, Mikel, Nathan, James A, Lehner, Paul J, Greenwood, Edward JD, McCaughan, Frank
• Format: Journal Article
• Language: English
• Published: United States Life Science Alliance 01.04.2022; Life Science Alliance LLC
• Subjects: ACE2; Administration, Topical; Androgen receptors; Androgens; Androgens - metabolism; Angiotensin; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - genetics; Angiotensin-Converting Enzyme 2 - metabolism; Antiviral Agents - pharmacology; Bioavailability; Cell differentiation; Cell surface; Cells, Cultured; Clinical trials; Coronaviruses; COVID-19; COVID-19 - prevention & control; COVID-19 - virology; Epithelial Cells; Esters - pharmacology; Experiments; Gene Expression; Goblet Cells - immunology; Goblet Cells - metabolism; Guanidines - pharmacology; Host-Pathogen Interactions - drug effects; Humans; Microscopy; Peptidyl-dipeptidase A; Prophylaxis; Proteinase inhibitors; Proteins; Respiratory Mucosa - drug effects; Respiratory Mucosa - metabolism; Respiratory Mucosa - virology; Respiratory tract; SARS-CoV-2 - drug effects; SARS-CoV-2 - physiology; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Serine proteinase; Serine Proteinase Inhibitors - administration & dosage; Severe acute respiratory syndrome coronavirus 2; Signal Transduction; Spike protein; Viral infections; Virus Internalization - drug effects; Virus Replication - drug effects; Japan
• ISSN: 2575-1077; 2575-1077
• DOI: 10.26508/lsa.202101116

Background: There are limited effective prophylactic/early treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Viral entry requires spike protein binding to the angiotensin-converting enzyme-2 receptor and cleavage by transmembrane serine protease 2 (TMPRSS2), a cell surface serine protease. Targeting of TMPRSS2 by either androgen blockade or direct inhibition is in clinical trials in early SARS-CoV-2 infection. Methods: We used differentiated primary human airway epithelial cells at the air–liquid interface to test the impact of targeting TMPRSS2 on the prevention of SARS-CoV-2 infection. Results: We first modelled the systemic delivery of compounds. Enzalutamide, an oral androgen receptor antagonist, had no impact on SARS-CoV-2 infection. By contrast, camostat mesylate, an orally available serine protease inhibitor, blocked SARS-CoV-2 entry. However, oral camostat is rapidly metabolised in the circulation, with poor airway bioavailability. We therefore modelled local airway administration by applying camostat to the apical surface of differentiated airway cultures. We demonstrated that a brief exposure to topical camostat effectively restricts SARS-CoV-2 infection. Conclusion: These experiments demonstrate a potential therapeutic role for topical camostat for pre- or post-exposure prophylaxis of SARS-CoV-2, which can now be evaluated in a clinical trial.