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

The Journal of Clinical Investigation
Young Joo SunVinit B Mahajan

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 repositio...Continue Reading

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Citations

Jul 12, 2021·The American Journal of Emergency Medicine·Rezan Karaali, Firdes Topal
Sep 23, 2021·Journal of Biomolecular Structure & Dynamics·Eldhose IypeMainak Dutta

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Software Mentioned

Maestro
MaxAlign
TREE
HMMER
HADDOCK
GraphPad Prism
Schrödinger
3DPhyloFold
PyMOL Molecular Graphics System
CD

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