Multiscale interactome analysis coupled with off-target drug predictions reveals drug repurposing candidates for human coronavirus disease

Scientific Reports, vol. 11, pp. 23315

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.

Authors 22

1. Michael G. Sugiyama

   Toronto Metropolitan University

   Affiliation as printed

   Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada

2. Haotian Cui

   University of Toronto · Vector Institute

   Affiliation as printed

   Department of Computer Science, University of Toronto, Toronto, ON, Canada

   Vector Institute, Toronto, ON, Canada

3. Dar’ya S. Redka
   Affiliation as printed

   Cyclica Inc., Toronto, ON, Canada

4. Mehran Karimzadeh

   Vector Institute

   Affiliation as printed

   Vector Institute, Toronto, ON, Canada

5. Edurne Rujas

   University of the Basque Country · University of Toronto · Hospital for Sick Children · Instituto Biofisika · Sickkids Research Institute

   Affiliation as printed

   Biofisika Institute (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Bilbao, Spain

   Department of Biochemistry, University of Toronto, Toronto, ON, Canada

   Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, Canada

6. Hassaan Maan

   University of Toronto · Vector Institute

   Affiliation as printed

   Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

   Peter Munk Cardiac Centre, University Health Centre, Toronto, ON, Canada

   Vector Institute, Toronto, ON, Canada

7. Sikander Hayat Aachen Institute of Experimental Medicine and Systems Biology

   RWTH Aachen University

   Affiliation as printed

   Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany

   Precision Cardiology Laboratory, Bayer US LLC, Cambridge, MA, USA

8. Kyle Cheung

   Toronto Metropolitan University

   Affiliation as printed

   Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada

   Graduate Program in Molecular Science, Ryerson University, Toronto, ON, Canada

9. Joseph B. McPhee

   Toronto Metropolitan University

   Affiliation as printed

   Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada

   Graduate Program in Molecular Science, Ryerson University, Toronto, ON, Canada

10. Russell D. Viirre

    Toronto Metropolitan University

    Affiliation as printed

    Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada

    Graduate Program in Molecular Science, Ryerson University, Toronto, ON, Canada

11. Andrew Haller

    University of Toronto

    Affiliation as printed

    Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada

    Phoenox Pharma, Toronto, ON, Canada

12. Roberto J. Botelho

    Toronto Metropolitan University

    Affiliation as printed

    Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada

    Graduate Program in Molecular Science, Ryerson University, Toronto, ON, Canada

13. Raffi Karshafian

    St. Michael's Hospital · Toronto Metropolitan University

    Affiliation as printed

    Department of Physics, Ryerson University, Toronto, ON, Canada

    Graduate Program in Molecular Science, Ryerson University, Toronto, ON, Canada

    Institute for Biomedical Engineering, Science and Technology (iBEST), a partnership between Ryerson University and St. Michael's Hospital, Toronto, ON, Canada

    Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, Canada

14. Sarah Sabatinos

    Toronto Metropolitan University

    Affiliation as printed

    Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada

    Graduate Program in Molecular Science, Ryerson University, Toronto, ON, Canada

15. Gregory D. Fairn

    St. Michael's Hospital · University of Toronto

    Affiliation as printed

    Department of Biochemistry, University of Toronto, Toronto, ON, Canada

    Department of Surgery, University of Toronto, Toronto, ON, Canada

    Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, Canada

16. Seyed Ali Madani Tonekaboni
    Affiliation as printed

    Cyclica Inc., Toronto, ON, Canada

17. Andreas Windemuth
    Affiliation as printed

    Cyclica Inc., Toronto, ON, Canada

18. Jean‐Philippe Julien

    University of Toronto · Hospital for Sick Children · Sickkids Research Institute

    Affiliation as printed

    Department of Biochemistry, University of Toronto, Toronto, ON, Canada

    Department of Immunology, Toronto, ON, Canada

    Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, Canada

19. Vijay M. Shahani
    Affiliation as printed

    Cyclica Inc., Toronto, ON, Canada

20. Stephen Scott MacKinnon corresponding
    Affiliation as printed

    Cyclica Inc., Toronto, ON, Canada. stephen.mackinnon@cyclicarx.com

    Cyclica Inc., Toronto, ON, Canada

21. Bo Wang corresponding

    University Health Network · University of Toronto · Vector Institute

    Affiliation as printed

    Department of Computer Science, University of Toronto, Toronto, ON, Canada. bowang@vectorinstitute.ai

    Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. bowang@vectorinstitute.ai

    Peter Munk Cardiac Centre, University Health Centre, Toronto, ON, Canada. bowang@vectorinstitute.ai

    Vector Institute, Toronto, ON, Canada. bowang@vectorinstitute.ai

    Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    Peter Munk Cardiac Centre, University Health Centre, Toronto, ON, Canada

22. Costin N. Antonescu corresponding

    St. Michael's Hospital · Toronto Metropolitan University

    Affiliation as printed

    Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada. cantonescu@ryerson.ca

    Graduate Program in Molecular Science, Ryerson University, Toronto, ON, Canada. cantonescu@ryerson.ca

    Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, Canada. cantonescu@ryerson.ca

    Graduate Program in Molecular Science, Ryerson University, Toronto, ON, Canada

    Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, Canada