RT Journal Article
SR Electronic
T1 Topical TMPRSS2 inhibition prevents SARS-CoV-2 infection in differentiated human airway cultures
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202101116
DO 10.26508/lsa.202101116
VO 5
IS 4
A1 Wenrui Guo
A1 Linsey M Porter
A1 Thomas WM Crozier
A1 Matthew Coates
A1 Akhilesh Jha
A1 Mikel McKie
A1 James A Nathan
A1 Paul J Lehner
A1 Edward JD Greenwood
A1 Frank McCaughan
YR 2022
UL https://www.life-science-alliance.org/content/5/4/e202101116.abstract
AB 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.