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Abstract
Understanding the mechanism of SARS‐CoV‐2 infection and identifying potential therapeutics are global imperatives. Using a quantitative systems pharmacology approach, we identified a set of repurposable and investigational drugs as potential therapeutics against COVID‐19. These were deduced from the gene expression signature of SARS‐CoV‐2‐infected A549 cells screened against Connectivity Map and prioritized by network proximity analysis with respect to disease modules in the viral–host interactome. We also identified immuno‐modulating compounds aiming at suppressing hyperinflammatory responses in severe COVID‐19 patients, based on the transcriptome of ACE2‐overexpressing A549 cells. Experiments with Vero‐E6 cells infected by SARS‐CoV‐2, as well as independent syncytia formation assays for probing ACE2/SARS‐CoV‐2 spike protein‐mediated cell fusion using HEK293T and Calu‐3 cells, showed that several predicted compounds had inhibitory activities. Among them, salmeterol, rottlerin, and mTOR inhibitors exhibited antiviral activities in Vero‐E6 cells; imipramine, linsitinib, hexylresorcinol, ezetimibe, and brompheniramine impaired viral entry. These novel findings provide new paths for broadening the repertoire of compounds pursued as therapeutics against COVID‐19.
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1 Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; School of Medicine, Tsinghua University, Beijing, China
2 Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; University of Pittsburgh Drug Discovery Institute, Pittsburgh, PA, USA
3 Department of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, Cedars‐Sinai Medical Center, Los Angeles, CA, USA; Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars‐Sinai Medical Center, Los Angeles, CA, USA
4 Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA, USA
5 Department of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, Cedars‐Sinai Medical Center, Los Angeles, CA, USA
6 Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
7 Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Division of Cardiology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA