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A systems-level study reveals host-targeted repurposable drugs against SARS-CoV-2 infection.
Chen, Fangyuan; Shi, Qingya; Pei, Fen; Vogt, Andreas; Porritt, Rebecca A; Garcia, Gustavo; Gomez, Angela C; Cheng, Mary Hongying; Schurdak, Mark E; Liu, Bing; Chan, Stephen Y; Arumugaswami, Vaithilingaraja; Stern, Andrew M; Taylor, D Lansing; Arditi, Moshe; Bahar, Ivet.
  • Chen F; Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • Shi Q; School of Medicine, Tsinghua University, Beijing, China.
  • Pei F; Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • Vogt A; School of Medicine, Tsinghua University, Beijing, China.
  • Porritt RA; Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • Garcia G; University of Pittsburgh Drug Discovery Institute, Pittsburgh, PA, USA.
  • Gomez AC; Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • Cheng MH; University of Pittsburgh Drug Discovery Institute, Pittsburgh, PA, USA.
  • Schurdak ME; Department of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Liu B; Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Chan SY; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • Arumugaswami V; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA, USA.
  • Stern AM; Department of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Taylor DL; Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • Arditi M; Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • Bahar I; University of Pittsburgh Drug Discovery Institute, Pittsburgh, PA, USA.
Mol Syst Biol ; 17(8): e10239, 2021 08.
Article in English | MEDLINE | ID: covidwho-1335457
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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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Drug Evaluation, Preclinical / Virus Internalization / COVID-19 Drug Treatment Type of study: Prognostic study Topics: Traditional medicine Limits: Animals / Humans Language: English Journal: Mol Syst Biol Journal subject: Molecular Biology / Biotechnology Year: 2021 Document Type: Article Affiliation country: Msb.202110239

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Drug Evaluation, Preclinical / Virus Internalization / COVID-19 Drug Treatment Type of study: Prognostic study Topics: Traditional medicine Limits: Animals / Humans Language: English Journal: Mol Syst Biol Journal subject: Molecular Biology / Biotechnology Year: 2021 Document Type: Article Affiliation country: Msb.202110239