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

Michael G. Sugiyama; Haotian Cui; Dar’ya S. Redka; Mehran Karimzadeh; Edurne Rujas; Hassaan Maan; Sikander Hayat; Kyle Cheung; Rahul Misra; Joseph B. McPhee; Russell D. Viirre; Andrew Haller; Roberto J. Botelho; Raffi Karshafian; Sarah A. Sabatinos; Gregory D. Fairn; Seyed Ali Madani Tonekaboni; Andreas Windemuth; Jean Philippe Julien; Vijay Shahani; Stephen S. MacKinnon; Bo Wang; Costin N. Antonescu

doi:10.1038/s41598-021-02432-7

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

Michael G. Sugiyama, Haotian Cui, Dar’ya S. Redka, Mehran Karimzadeh, Edurne Rujas, Hassaan Maan, Sikander Hayat, Kyle Cheung, Rahul Misra, Joseph B. McPhee, Russell D. Viirre, Andrew Haller, Roberto J. Botelho, Raffi Karshafian, Sarah A. Sabatinos, Gregory D. Fairn, Seyed Ali Madani Tonekaboni, Andreas Windemuth, Jean Philippe Julien, Vijay ShahaniStephen S. MacKinnon, Bo Wang, Costin N. Antonescu

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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.

Original language	English
Article number	23315
Journal	Scientific Reports
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41598-021-02432-7
Publication status	Published - Dec 2021
Externally published	Yes

Bibliographical note

Funding Information:
We gratefully acknowledge funding that supported this research support from the Ryerson University Faculty of Science (CNA), as well as funding support in the form of a CIFAR Catalyst Grant (JPJ and CNA), an NSERC Alliance Grant (CNA) and the Ryerson COVID-19 SRC Response Fund award (CNA). BW is partly supported by CIFAR AI Chairs Program. This work was also supported by a Mitacs award (BW), the European Union’s Horizon 2020 research and innovation program under a Marie Sklodowska-Curie grant (ER), by the CIFAR Azrieli Global Scholar program (JPJ), by the Ontario Early Researcher Awards program (JPJ and CNA), and by the Canada Research Chairs program (JPJ). We also thank Dr. James Rini (University of Toronto) for the kind gift of the 9.8E12 antibody used to detect the 229E Spike protein, and Dr. Scott Gray-Owen (University of Toronto) for the kind gift of the NL63 human coronavirus.

Publisher Copyright:
© 2021, The Author(s).

ASJC Scopus Subject Areas

General

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41598-021-02432-7

Cite this

Sugiyama, M. G., Cui, H., Redka, D. S., Karimzadeh, M., Rujas, E., Maan, H., Hayat, S., Cheung, K., Misra, R., McPhee, J. B., Viirre, R. D., Haller, A., Botelho, R. J., Karshafian, R., Sabatinos, S. A., Fairn, G. D., Madani Tonekaboni, S. A., Windemuth, A., Julien, J. P., ... Antonescu, C. N. (2021). Multiscale interactome analysis coupled with off-target drug predictions reveals drug repurposing candidates for human coronavirus disease. Scientific Reports, 11(1), Article 23315. https://doi.org/10.1038/s41598-021-02432-7

Sugiyama, MG, Cui, H, Redka, DS, Karimzadeh, M, Rujas, E, Maan, H, Hayat, S, Cheung, K, Misra, R, McPhee, JB, Viirre, RD, Haller, A, Botelho, RJ, Karshafian, R, Sabatinos, SA, Fairn, GD, Madani Tonekaboni, SA, Windemuth, A, Julien, JP, Shahani, V, MacKinnon, SS, Wang, B & Antonescu, CN 2021, 'Multiscale interactome analysis coupled with off-target drug predictions reveals drug repurposing candidates for human coronavirus disease', Scientific Reports, vol. 11, no. 1, 23315. https://doi.org/10.1038/s41598-021-02432-7

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

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.",

author = "Sugiyama, {Michael G.} and Haotian Cui and Redka, {Dar{\textquoteright}ya S.} and Mehran Karimzadeh and Edurne Rujas and Hassaan Maan and Sikander Hayat and Kyle Cheung and Rahul Misra and McPhee, {Joseph B.} and Viirre, {Russell D.} and Andrew Haller and Botelho, {Roberto J.} and Raffi Karshafian and Sabatinos, {Sarah A.} and Fairn, {Gregory D.} and {Madani Tonekaboni}, {Seyed Ali} and Andreas Windemuth and Julien, {Jean Philippe} and Vijay Shahani and MacKinnon, {Stephen S.} and Bo Wang and Antonescu, {Costin N.}",

note = "Funding Information: We gratefully acknowledge funding that supported this research support from the Ryerson University Faculty of Science (CNA), as well as funding support in the form of a CIFAR Catalyst Grant (JPJ and CNA), an NSERC Alliance Grant (CNA) and the Ryerson COVID-19 SRC Response Fund award (CNA). BW is partly supported by CIFAR AI Chairs Program. This work was also supported by a Mitacs award (BW), the European Union{\textquoteright}s Horizon 2020 research and innovation program under a Marie Sklodowska-Curie grant (ER), by the CIFAR Azrieli Global Scholar program (JPJ), by the Ontario Early Researcher Awards program (JPJ and CNA), and by the Canada Research Chairs program (JPJ). We also thank Dr. James Rini (University of Toronto) for the kind gift of the 9.8E12 antibody used to detect the 229E Spike protein, and Dr. Scott Gray-Owen (University of Toronto) for the kind gift of the NL63 human coronavirus. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

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doi = "10.1038/s41598-021-02432-7",

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AU - Sugiyama, Michael G.

AU - Cui, Haotian

AU - Redka, Dar’ya S.

AU - Karimzadeh, Mehran

AU - Rujas, Edurne

AU - Maan, Hassaan

AU - Hayat, Sikander

AU - Cheung, Kyle

AU - Misra, Rahul

AU - McPhee, Joseph B.

AU - Viirre, Russell D.

AU - Haller, Andrew

AU - Botelho, Roberto J.

AU - Karshafian, Raffi

AU - Sabatinos, Sarah A.

AU - Fairn, Gregory D.

AU - Madani Tonekaboni, Seyed Ali

AU - Windemuth, Andreas

AU - Julien, Jean Philippe

AU - Shahani, Vijay

AU - MacKinnon, Stephen S.

AU - Wang, Bo

AU - Antonescu, Costin N.

N1 - Funding Information: We gratefully acknowledge funding that supported this research support from the Ryerson University Faculty of Science (CNA), as well as funding support in the form of a CIFAR Catalyst Grant (JPJ and CNA), an NSERC Alliance Grant (CNA) and the Ryerson COVID-19 SRC Response Fund award (CNA). BW is partly supported by CIFAR AI Chairs Program. This work was also supported by a Mitacs award (BW), the European Union’s Horizon 2020 research and innovation program under a Marie Sklodowska-Curie grant (ER), by the CIFAR Azrieli Global Scholar program (JPJ), by the Ontario Early Researcher Awards program (JPJ and CNA), and by the Canada Research Chairs program (JPJ). We also thank Dr. James Rini (University of Toronto) for the kind gift of the 9.8E12 antibody used to detect the 229E Spike protein, and Dr. Scott Gray-Owen (University of Toronto) for the kind gift of the NL63 human coronavirus. Publisher Copyright: © 2021, The Author(s).

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

Abstract

Bibliographical note

ASJC Scopus Subject Areas

PubMed: MeSH publication types

UN SDGs

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