Topical TMPRSS2 inhibition prevents SARS-CoV-2 infection in differentiated human airway cultures
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 ce...
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| Published in | Life science alliance Vol. 5; no. 4; p. e202101116 |
|---|---|
| Main Authors | , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Life Science Alliance
01.04.2022
Life Science Alliance LLC |
| Subjects | |
| Online Access | Get full text |
| ISSN | 2575-1077 2575-1077 |
| DOI | 10.26508/lsa.202101116 |
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| 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. |
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| AbstractList | There is an urgent need to develop novel therapeutic strategies to prevent viral transmission and COVID-19 disease—we show that topical application of camostat, a TMPRSS2 inhibitor, could be a simple, safe, and effective strategy for restricting upper airway infection.
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. 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. 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.BACKGROUNDThere 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.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.METHODSWe 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.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.RESULTSWe 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.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.CONCLUSIONThese 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. 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. 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. 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. 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. |
| Author | Crozier, Thomas WM Porter, Linsey M Nathan, James A Guo, Wenrui McKie, Mikel Greenwood, Edward JD Jha, Akhilesh Lehner, Paul J Coates, Matthew McCaughan, Frank |
| AuthorAffiliation | 1 Department of Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge, UK 2 Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK 3 Medical Research Council, Biostatistic Unit, Cambridge, UK |
| AuthorAffiliation_xml | – name: 2 Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK – name: 1 Department of Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge, UK – name: 3 Medical Research Council, Biostatistic Unit, Cambridge, UK |
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| Snippet | Background: There are limited effective prophylactic/early treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Viral entry... There are limited effective prophylactic/early treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Viral entry requires... There is an urgent need to develop novel therapeutic strategies to prevent viral transmission and COVID-19 disease—we show that topical application of... |
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| SubjectTerms | 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 |
| Title | Topical TMPRSS2 inhibition prevents SARS-CoV-2 infection in differentiated human airway cultures |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/35110354 https://www.proquest.com/docview/3251399653 https://www.proquest.com/docview/2625260752 https://pubmed.ncbi.nlm.nih.gov/PMC8814636 |
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