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

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

  • Nat Commun. 2021 Jun 23;12(1):3907. doi: 10.1038/s41467-021-24156-y.
Yanwen Chen  # 1 2,  Travis B Lear  # 1 3 4,  John W Evankovich  # 1 3,  Mads B Larsen 1,  Bo Lin 1,  Irene Alfaras 1,  Jason R Kennerdell 1,  Laura Salminen 1,  Daniel P Camarco 1,  Karina C Lockwood 1,  Ferhan Tuncer 1,  Jie Liu 1,  Michael M Myerburg 3,  John F McDyer 3,  Yuan Liu 5 6 7,  Toren Finkel 8 9 10,  Bill B Chen 11 12 13
Affiliations

Affiliations

  • 1 Aging Institute, University of Pittsburgh/UPMC, Pittsburgh, PA, USA.
  • 2 Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 3 Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA, USA.
  • 4 Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA.
  • 5 Aging Institute, University of Pittsburgh/UPMC, Pittsburgh, PA, USA. liuy13@upmc.edu.
  • 6 Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA, USA. liuy13@upmc.edu.
  • 7 McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA. liuy13@upmc.edu.
  • 8 Aging Institute, University of Pittsburgh/UPMC, Pittsburgh, PA, USA. finkelt@pitt.edu.
  • 9 Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA. finkelt@pitt.edu.
  • 10 Department of Medicine, Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA. finkelt@pitt.edu.
  • 11 Aging Institute, University of Pittsburgh/UPMC, Pittsburgh, PA, USA. chenb@upmc.edu.
  • 12 Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA, USA. chenb@upmc.edu.
  • 13 Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA. chenb@upmc.edu.
  • # Contributed equally.
PMID: 34162861 DOI: 10.1038/s41467-021-24156-y
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.

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