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

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

doi:10.1038/s41598-021-02432-7

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.

Highlights

The COVID-19 pandemic has highlighted the urgent need for the identification of new antiviral drug therapies for a variety of diseases
severe acute respiratory syndrome (SARS)-CoV-2, SARS-CoV-1 and NL63 enter cells by using their Spike (S) outer protein, which interacts with angiotensin converting enzyme 2 (ACE2) on host cells[8,9,10,11], while 229E and OC43 depend on host cell aminopeptidase N and glycosaminoglycans, respectively[12,13]
To further characterize the antiviral activity of capmatinib on human coronaviruses, we developed several complementary cell-based assays to probe the different aspects of infection by several different human coronaviruses, including 229E, OC43, and NL63

Summary

Introduction

The COVID-19 pandemic has highlighted the urgent need for the identification of new antiviral drug therapies for a variety of diseases. For SARS-CoV-2, 26 viral proteins were found to interact with 332 host cell proteins, spanning a range of functions including membrane trafficking, centrosome structure and function, membrane transport, DNA replication and stress granule formation[23]. This viral protein interactome provides a rich source of information from which to identify host proteins that are functionally important for viral entry and replication and may serve as antiviral drug targets. The virus/host protein interactome and the identification of proteins functionally required for viral entry and replication of common cold coronaviruses may reveal important novel pan-human coronavirus antiviral drug targets

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Conclusion