1. Academic Validation
  2. Structure-based phylogeny identifies avoralstat as a TMPRSS2 inhibitor that prevents SARS-CoV-2 infection in mice

Structure-based phylogeny identifies avoralstat as a TMPRSS2 inhibitor that prevents SARS-CoV-2 infection in mice

  • J Clin Invest. 2021 May 17;131(10):e147973. doi: 10.1172/JCI147973.
Young Joo Sun 1 Gabriel Velez 1 2 Dylan E Parsons 1 3 Kun Li 4 Miguel E Ortiz 4 Shaunik Sharma 4 Paul B McCray Jr 4 5 Alexander G Bassuk 4 6 7 Vinit B Mahajan 1 8
Affiliations

Affiliations

  • 1 Molecular Surgery Lab, Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, California, USA.
  • 2 Medical Scientist Training Program, University of Iowa, Iowa City, Iowa, USA.
  • 3 Stanford ChEM-H Medicinal Chemistry Knowledge Center, Stanford University, Palo Alto, California, USA.
  • 4 Department of Pediatrics.
  • 5 Department of Microbiology and Immunology.
  • 6 Department of Neurology, and.
  • 7 Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa, USA.
  • 8 Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA.
Abstract

Drugs targeting host proteins can act prophylactically to reduce viral burden early in disease and limit morbidity, even with antivirals and vaccination. Transmembrane serine Protease 2 (TMPRSS2) is a human Protease required for SARS coronavirus 2 (SARS-CoV-2) viral entry and may represent such a target. We hypothesized that drugs selected from proteins related by their tertiary structure, rather than their primary structure, were likely to interact with TMPRSS2. We created a structure-based phylogenetic computational tool named 3DPhyloFold to systematically identify structurally similar serine proteases with known therapeutic inhibitors and demonstrated effective inhibition of SARS-CoV-2 Infection in vitro and in vivo. Several candidate compounds, avoralstat, PCI-27483, antipain, and soybean trypsin inhibitor, inhibited TMPRSS2 in biochemical and cell Infection assays. Avoralstat, a clinically tested kallikrein-related B1 inhibitor, inhibited SARS-CoV-2 entry and replication in human airway epithelial cells. In an in vivo proof of principle, avoralstat significantly reduced lung tissue titers and mitigated weight loss when administered prophylactically to mice susceptible to SARS-CoV-2, indicating its potential to be repositioned for coronavirus disease 2019 (COVID-19) prophylaxis in humans.

Keywords

COVID-19; Drug screens; Infectious disease; Molecular biology; Proteases.

Figures
Products