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

Abstract

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.

• Authors: Wenrui Guo, Linsey M Porter, Thomas Wm Crozier, Matthew Coates, Akhilesh Jha, Mikel McKie, James A Nathan, Paul J Lehner, Edward Jd Greenwood, Frank McCaughan
• Journal: Life science alliance (Life Sci Alliance) Vol. 5 Issue 4 (04 2022) ISSN: 2575-1077 [Electronic] United States
• PMID: 35110354 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 Guo et al.

Chemical References

• Androgens
• Antiviral Agents
• Esters
• Guanidines
• Serine Proteinase Inhibitors
• camostat
• ACE2 protein, human
• Angiotensin-Converting Enzyme 2
• Serine Endopeptidases
• TMPRSS2 protein, human

Topics

• Administration, Topical
• Androgens (metabolism)
• Angiotensin-Converting Enzyme 2 (genetics, metabolism)
• Antiviral Agents (pharmacology)
• COVID-19 (prevention & control, virology)
• Cells, Cultured
• Epithelial Cells
• Esters (pharmacology)
• Gene Expression
• Goblet Cells (immunology, metabolism)
• Guanidines (pharmacology)
• Host-Pathogen Interactions (drug effects)
• Humans
• Respiratory Mucosa (drug effects, metabolism, virology)
• SARS-CoV-2 (drug effects, physiology)
• Serine Endopeptidases (genetics, metabolism)
• Serine Proteinase Inhibitors (administration & dosage)
• Signal Transduction
• Virus Internalization (drug effects)
• Virus Replication (drug effects)