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Topical TMPRSS2 inhibition prevents SARS-CoV-2 infection in differentiated human airway cultures.
Life Sci Alliance. 2022 04; 5(4)LS

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.

Links

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Authors+Show Affiliations

Guo W
Department of Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge, UK.
Porter LM
Department of Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge, UK.
Crozier TW
Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK.
Coates M
Department of Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge, UK.
Jha A
Department of Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge, UK.
McKie M
Medical Research Council, Biostatistic Unit, Cambridge, UK.
Nathan JA
Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK.
Lehner PJ
Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK.
Greenwood EJ
Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK fm319@cam.ac.uk.
McCaughan F
Department of Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge, UK ejdg2@cam.ac.uk.

MeSH

Administration, TopicalAndrogensAngiotensin-Converting Enzyme 2Antiviral AgentsCOVID-19Cells, CulturedEpithelial CellsEstersGene ExpressionGoblet CellsGuanidinesHost-Pathogen InteractionsHumansRespiratory MucosaSARS-CoV-2Serine EndopeptidasesSerine Proteinase InhibitorsSignal TransductionVirus InternalizationVirus Replication

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

35110354

Citation

Guo, Wenrui, et al. "Topical TMPRSS2 Inhibition Prevents SARS-CoV-2 Infection in Differentiated Human Airway Cultures." Life Science Alliance, vol. 5, no. 4, 2022.
Guo W, Porter LM, Crozier TW, et al. Topical TMPRSS2 inhibition prevents SARS-CoV-2 infection in differentiated human airway cultures. Life Sci Alliance. 2022;5(4).
Guo, W., Porter, L. M., Crozier, T. W., Coates, M., Jha, A., McKie, M., Nathan, J. A., Lehner, P. J., Greenwood, E. J., & McCaughan, F. (2022). Topical TMPRSS2 inhibition prevents SARS-CoV-2 infection in differentiated human airway cultures. Life Science Alliance, 5(4). https://doi.org/10.26508/lsa.202101116
Guo W, et al. Topical TMPRSS2 Inhibition Prevents SARS-CoV-2 Infection in Differentiated Human Airway Cultures. Life Sci Alliance. 2022;5(4) PubMed PMID: 35110354.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Topical TMPRSS2 inhibition prevents SARS-CoV-2 infection in differentiated human airway cultures. AU - Guo,Wenrui, AU - Porter,Linsey M, AU - Crozier,Thomas Wm, AU - Coates,Matthew, AU - Jha,Akhilesh, AU - McKie,Mikel, AU - Nathan,James A, AU - Lehner,Paul J, AU - Greenwood,Edward Jd, AU - McCaughan,Frank, Y1 - 2022/02/02/ PY - 2021/05/09/received PY - 2022/01/04/revised PY - 2022/01/05/accepted PY - 2022/2/3/entrez PY - 2022/2/4/pubmed PY - 2022/2/9/medline JF - Life science alliance JO - Life Sci Alliance VL - 5 IS - 4 N2 - 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. SN - 2575-1077 UR - https://www.unboundmedicine.com/medline/citation/35110354/Topical_TMPRSS2_inhibition_prevents_SARS_CoV_2_infection_in_differentiated_human_airway_cultures_ DB - PRIME DP - Unbound Medicine ER -