Potential antiviral options against SARS-CoV-2 infection

  1. Aleksandr Ianevski
  2. Rouan Yao
  3. Mona Høysæter Fenstad
  4. Svetlana Biza
  5. Eva Zusinaite
  6. Tuuli Reisberg
  7. Hilde Lysvand
  8. Kirsti Løseth
  9. Veslemøy Malm Landsem
  10. Janne Fossum Malmring
  11. Valentyn Oksenych
  12. Sten Even Erlandsen
  13. Per Arne Aas
  14. Lars Hagen
  15. Caroline H. Pettersen
  16. Tanel Tenson
  17. Jan Egil Afset
  18. Svein Arne Nordbø
  19. Magnar Bjørås
  20. Denis E. Kainov

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Abstract

As of June 2020, the number of people infected with severe acute respiratory coronavirus 2 (SARS-CoV-2) continues to skyrocket, with more than 6,5 million cases worldwide. Both the World Health Organization (WHO) and United Nations (UN) has highlighted the need for better control of SARS-CoV-2 infections. However, developing novel virus-specific vaccines, monoclonal antibodies and antiviral drugs against SARS-CoV-2 can be time-consuming and costly. Convalescent sera and safe-in-man broad-spectrum antivirals (BSAAs) are readily available treatment options. Here we developed a neutralization assay using SARS-CoV-2 strain and Vero-E6 cells. We identified most potent sera from recovered patients for treatment of SARS-CoV-2-infected patients. We also screened 136 safe-in-man broad-spectrum antivirals against SARS-CoV-2 infection in Vero-E6 cells and identified nelfinavir, salinomycin, amodiaquine, obatoclax, emetine and homoharringtonine. We found that combinations of virus-directed nelfinavir along with host-directed amodiaquine exhibited the highest synergy. Finally, we developed a website to disseminate the knowledge on available and emerging treatments of COVID-19.

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  1. ScreenIT

    SciScore for 10.1101/2020.05.12.091165: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementConsent: The patients gave their informed consent through the koronastudien.no website.
    IRB: The study was approved by national ethical committee (clinical trial: NCT04320732; REK: 124170). 2.1.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Cell cultures: Human telomerase reverse transcriptase-immortalized retinal pigment epithelial RPE, lung adenocarcinoma A427, non-small-cell lung cancer Calu-3 and epithelial colorectal adenocarcinoma Caco-2 cells were grown in DMEM-F12 medium supplemented with 100 μg/mL streptomycin and 100 U/mL penicillin (Pen/Strep), 2 mM L-glutamine, 10% FBS, and 0.25% sodium bicarbonate (Sigma-Aldrich, St. Louis, USA).
    Caco-2
    suggested: None
    Human large-cell lung carcinoma NCI-H460, colon cancer SW620, colorectal carcinoma SW480 and HT29 cells were grown in RPMI medium supplied with 10% FBS and Pen-Strep.
    NCI-H460
    suggested: None
    SW480
    suggested: None
    HT29
    suggested: None
    Human adenocarcinoma alveolar basal epithelial A549, human embryonic kidney HEK-293 cells and kidney epithelial cells extracted from an African green monkey (Vero-E6) were grown in DMEM medium supplemented with 10% FBS and Pen-Strep.
    A549
    suggested: None
    HEK-293
    suggested: None
    200 μl of nasopharyngeal swabs (NPS) in universal transport medium were diluted 5 times in culture medium (DMEM) supplemented with 0.2% bovine serum albumin (BSA), 0.6 μg/mL penicillin, 60 μg/mL streptomycin, and 2 mM L-glutamine and inoculated into Vero E6 cells.
    Vero E6
    suggested: RRID:CVCL_XD71)
    Table S1: Compounds, their suppliers, catalogue numbers and AUCs; Table S2: Results of neutralization and ELISA assays; Figure S1: Propagation of HCoV-19/Norway/Trondheim-E9/2020 in cell cultures; Figure S2: Effect of temperature and UV radiation on infectivity of HCoV-19/Norway/Trondheim-E9/2020 strain; Figure S3: The effect of serum from patient recovered from SARS-CoV-2 infection on viability of Vero-E6 cells infected with 7 SARS-CoV-2 strains; Figure S4: Comparison of anti-SARS-CoV-2 activities of amodiaquine and its analogues.
    Vero-E6
    suggested: None
    Software and Algorithms
    SentencesResources
    Reads were aligned using the Bowtie 2 software package version 2.3.4.1 to the reference viral genome Wuhan-Hu-1/2019.
    Bowtie 2
    suggested: (Bowtie 2, RRID:SCR_016368)
    The consensus FASTQ sequences were obtained with bcftools and vcfutils.pl (from SAMtools) and converted to FASTA using seqtk (https://github.com/lh3/seqtk).
    SAMtools
    suggested: (SAMTOOLS, RRID:SCR_002105)
    Drug and serum sensitivity quantification: The half-maximal cytotoxic concentration (CC50) for each compound was calculated based on viability/death curves obtained on mock-infected cells after non-linear regression analysis with a variable slope using GraphPad Prism software version 7.0a (GraphPad Software, CA, USA).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    The expected responses were calculated based on ZIP reference model using SynergyFinder web-application, version 2 [80]. 2.10.
    SynergyFinder
    suggested: (SynergyFinder, RRID:SCR_019318)
    2.11. https://sars-coronavirus-2.info/ website: We reviewed the current landscape of available diagnostic tools, as well as emerging treatment and prophylactic options for the SARS-CoV-2 pandemic and have summarized the information in a database that can be freely accessed at https://sars-coronavirus-2.info. The information in the database was obtained from PubMed, clinicaltrials.gov, DrugBank, DrugCentral, Chinese Clinical Trials Register (ChiCTR), and EU Clinical Trials Register databases [25–27] as well as other public sources.
    PubMed
    suggested: (PubMed, RRID:SCR_004846)
    DrugBank
    suggested: (DrugBank, RRID:SCR_002700)

    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: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04252664SuspendedA Trial of Remdesivir in Adults With Mild and Moderate COVID…
    NCT0425487Trial number did not resolve on clinicaltrials.gov. Is the number correct?NA
    NCT04255017RecruitingA Prospective/Retrospective,Randomized Controlled Clinical S…
    NCT04261517CompletedEfficacy and Safety of Hydroxychloroquine for Treatment of C…
    NCT04260594Not yet recruitingClinical Study of Arbidol Hydrochloride Tablets in the Treat…
    NCT04320732RecruitingRisk Factors for Community- and Workplace Transmission of CO…

    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.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2020.05.12.091165v3 on bioRxiv
  3. Version published to 10.1101/2020.05.12.091165v2 on bioRxiv
  4. Version published to 10.1101/2020.05.12.091165v1 on bioRxiv