A high-throughput screen for TMPRSS2 expression identifies FDA-approved compounds that can limit SARS-CoV-2 entry

Yanwen Chen, Travis B. Lear, John W. Evankovich, Mads B. Larsen, Bo Lin, Irene Alfaras, Jason R. Kennerdell, Laura Salminen, Daniel P. Camarco, Karina C. Lockwood, Ferhan Tuncer, Jie Liu, Michael M. Myerburg, John F. McDyer, Yuan Liu (), Toren Finkel () and Bill B. Chen ()
Additional contact information
Yanwen Chen: University of Pittsburgh/UPMC
Travis B. Lear: University of Pittsburgh/UPMC
John W. Evankovich: University of Pittsburgh/UPMC
Mads B. Larsen: University of Pittsburgh/UPMC
Bo Lin: University of Pittsburgh/UPMC
Irene Alfaras: University of Pittsburgh/UPMC
Jason R. Kennerdell: University of Pittsburgh/UPMC
Laura Salminen: University of Pittsburgh/UPMC
Daniel P. Camarco: University of Pittsburgh/UPMC
Karina C. Lockwood: University of Pittsburgh/UPMC
Ferhan Tuncer: University of Pittsburgh/UPMC
Jie Liu: University of Pittsburgh/UPMC
Michael M. Myerburg: University of Pittsburgh
John F. McDyer: University of Pittsburgh
Yuan Liu: University of Pittsburgh/UPMC
Toren Finkel: University of Pittsburgh/UPMC
Bill B. Chen: University of Pittsburgh/UPMC

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract SARS-CoV-2 (2019-nCoV) is the pathogenic coronavirus responsible for the global pandemic of COVID-19 disease. The Spike (S) protein of SARS-CoV-2 attaches to host lung epithelial cells through the cell surface receptor ACE2, a process dependent on host proteases including TMPRSS2. Here, we identify small molecules that reduce surface expression of TMPRSS2 using a library of 2,560 FDA-approved or current clinical trial compounds. We identify homoharringtonine and halofuginone as the most attractive agents, reducing endogenous TMPRSS2 expression at sub-micromolar concentrations. These effects appear to be mediated by a drug-induced alteration in TMPRSS2 protein stability. We further demonstrate that halofuginone modulates TMPRSS2 levels through proteasomal-mediated degradation that involves the E3 ubiquitin ligase component DDB1- and CUL4-associated factor 1 (DCAF1). Finally, cells exposed to homoharringtonine and halofuginone, at concentrations of drug known to be achievable in human plasma, demonstrate marked resistance to SARS-CoV-2 infection in both live and pseudoviral in vitro models. Given the safety and pharmacokinetic data already available for the compounds identified in our screen, these results should help expedite the rational design of human clinical trials designed to combat active COVID-19 infection.

Date: 2021
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DOI: 10.1038/s41467-021-24156-y

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