Multiscale interactome analysis coupled with off‑target drug predictions reveals drug repurposing candidates for human coronavirus disease
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Abstract
<p> </p> <p>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.</p> <p> </p>
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SciScore for 10.1101/2021.04.13.439274: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Antibodies Sentences Resources 229E S protein was detected with treating the cells with 100 μL (1:50 dilution) of the mouse anti-229E S protein antibody 9.8E12 90 by the inverted drop technique for 1 h at room temperature. anti-229E S proteinsuggested: NoneFollowing primary antibody incubation, cells were washed and treated with AlexaFluor488-conjugated anti-mouse secondary antibody (1:1000 dilution) (Cedarlane Labs Cat. No. 115-545-003) and DAPI (1 μg/mL) for 1 hour at room temperature. anti-mousesuggested: (Jackson ImmunoResearch Labs Cat# 115-545-003, RRID:AB_2338840)Experimental Models: Cell Lines Sentences Resources Briefly, MRC-5 … SciScore for 10.1101/2021.04.13.439274: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Antibodies Sentences Resources 229E S protein was detected with treating the cells with 100 μL (1:50 dilution) of the mouse anti-229E S protein antibody 9.8E12 90 by the inverted drop technique for 1 h at room temperature. anti-229E S proteinsuggested: NoneFollowing primary antibody incubation, cells were washed and treated with AlexaFluor488-conjugated anti-mouse secondary antibody (1:1000 dilution) (Cedarlane Labs Cat. No. 115-545-003) and DAPI (1 μg/mL) for 1 hour at room temperature. anti-mousesuggested: (Jackson ImmunoResearch Labs Cat# 115-545-003, RRID:AB_2338840)Experimental Models: Cell Lines Sentences Resources Briefly, MRC-5 or LLC-MK2 cells were grown to 90% confluence in a T75 tissue culture flask in standard growth medium. LLC-MK2suggested: NoneBriefly, MRC-5 cells were grown to 40% confluency before the first round of transfection. MRC-5suggested: NoneBriefly, PsVs were produced by transfection of human kidney HEK293T cells with the full-length SARS-CoV-2 spike (BEI NR52310) or SARS-CoV-1 spike (kindly provided by S. Pöhlmann, Leibniz Institute for Primate Research, Göttingen, Germany). HEK293Tsuggested: NoneIn order to confirm that the reduced infection was not related to cell toxicity, HeLa-ACE2 cell viability upon incubation with serial dilutions of the small molecules was assessed. 10,000 cells/ well of pre-seeded HeLa-ACE2 cells were co-cultured with 2-fold serial dilutions of the small molecules at 37 °C for 48h-60h under the same conditions as in the neutralization assay. HeLa-ACE2suggested: NoneSoftware and Algorithms Sentences Resources The compound screening library consists of 10,244 small molecule drugs, retrieved from DrugBank 88 on February 19th, 2020. DrugBanksuggested: (DrugBank, RRID:SCR_002700)) RDKit: Open-source cheminformatics; http://www.rdkit.org) 89. http://www.rdkit.orgsuggested: (RDKit: Open-Source Cheminformatics Software, RRID:SCR_014274)Methods 2 and 3 combined the GCN for viral-host target selection and PolypharmDB to predict small molecule binders for the proposed targets. PolypharmDBsuggested: NoneMethod 3 ranked all PolyphamDB compounds according to a weighted aggregate score combining all ten GCN targets. PolyphamDBsuggested: NoneSlides were visualized on an inverted microscope by widefield epifluorescence (Leica DMi8 microscope, Andor Zyla 4.2-megapixel camera, run by Quorum WaveFX by Metamorph software). Metamorphsuggested: NoneImages were quantified by measuring the total fluorescence signal using ImageJ software (National Institutes of Health, Bethesda, MD) 91. qRT-PCR detection of NL63: LLC-MK2 cells seeded on 6-well tissue culture plates were infected with NL63 at a MOI of 0.01 for a 1 h adsorption period in the presence of 10 μM capmatinib in a volume of 300 μL. ImageJsuggested: (ImageJ, RRID:SCR_003070)IC50 values were calculated using Prism. Prismsuggested: (PRISM, RRID:SCR_005375)Statistical Analysis: All statistical analysis for biological experiments were performed with GraphPad Prism 9 software using student t-tests when comparing two conditions (Figs 3B, 3D, 3E, 4B, 4E, 4F, 4G, S2A) or one-way ANOVA with Tukey post-hoc test when comparing multiple conditions (Figs. 3A, 3C, 4A, 4C, S4). GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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