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Multiscale interactome analysis coupled with off-target drug predictions reveals drug repurposing candidates for human coronavirus disease.
Sugiyama, Michael G; Cui, Haotian; Redka, Dar'ya S; Karimzadeh, Mehran; Rujas, Edurne; Maan, Hassaan; Hayat, Sikander; Cheung, Kyle; Misra, Rahul; McPhee, Joseph B; Viirre, Russell D; Haller, Andrew; Botelho, Roberto J; Karshafian, Raffi; Sabatinos, Sarah A; Fairn, Gregory D; Madani Tonekaboni, Seyed Ali; Windemuth, Andreas; Julien, Jean-Philippe; Shahani, Vijay; MacKinnon, Stephen S; Wang, Bo; Antonescu, Costin N.
  • Sugiyama MG; Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada.
  • Cui H; Department of Computer Science, University of Toronto, Toronto, ON, Canada.
  • Redka DS; Vector Institute, Toronto, ON, Canada.
  • Karimzadeh M; Cyclica Inc., Toronto, ON, Canada.
  • Rujas E; Vector Institute, Toronto, ON, Canada.
  • Maan H; Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, Canada.
  • Hayat S; Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
  • Cheung K; Biofisika Institute (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Bilbao, Spain.
  • Misra R; Vector Institute, Toronto, ON, Canada.
  • McPhee JB; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
  • Viirre RD; Peter Munk Cardiac Centre, University Health Centre, Toronto, ON, Canada.
  • Haller A; Precision Cardiology Laboratory, Bayer US LLC, Cambridge, MA, USA.
  • Botelho RJ; Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany.
  • Karshafian R; Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada.
  • Sabatinos SA; Graduate Program in Molecular Science, Ryerson University, Toronto, ON, Canada.
  • Fairn GD; Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada.
  • Madani Tonekaboni SA; Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada.
  • Windemuth A; Graduate Program in Molecular Science, Ryerson University, Toronto, ON, Canada.
  • Julien JP; Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada.
  • Shahani V; Graduate Program in Molecular Science, Ryerson University, Toronto, ON, Canada.
  • MacKinnon SS; Phoenox Pharma, Toronto, ON, Canada.
  • Wang B; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
  • Antonescu CN; Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada.
Sci Rep ; 11(1): 23315, 2021 12 02.
Article in English | MEDLINE | ID: covidwho-1550334
ABSTRACT
The COVID-19 pandemic has highlighted the urgent need for the identification of new antiviral drug therapies for a variety of diseases. COVID-19 is caused by infection with the human coronavirus SARS-CoV-2, while other related human coronaviruses cause diseases ranging from severe respiratory infections to the common cold. We developed a computational approach to identify new antiviral drug targets and repurpose clinically-relevant drug compounds for the treatment of a range of human coronavirus diseases. Our approach is based on graph convolutional networks (GCN) and involves multiscale host-virus interactome analysis coupled to off-target drug predictions. Cell-based experimental assessment reveals several clinically-relevant drug repurposing candidates predicted by the in silico analyses to have antiviral activity against human coronavirus infection. In particular, we identify the MET inhibitor capmatinib as having potent and broad antiviral activity against several coronaviruses in a MET-independent manner, as well as novel roles for host cell proteins such as IRAK1/4 in supporting human coronavirus infection, which can inform further drug discovery studies.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Coronavirus / Drug Repositioning / Drug Development Type of study: Prognostic study Limits: Humans Language: English Journal: Sci Rep Year: 2021 Document Type: Article Affiliation country: S41598-021-02432-7

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Coronavirus / Drug Repositioning / Drug Development Type of study: Prognostic study Limits: Humans Language: English Journal: Sci Rep Year: 2021 Document Type: Article Affiliation country: S41598-021-02432-7