Identification of novel antiviral drug combinations in vitro and tracking their development

  1. Aleksandr Ianevski
  2. Rouan Yao
  3. Svetlana Biza
  4. Eva Zusinaite
  5. Andres Männik
  6. Gaily Kivi
  7. Anu Planken
  8. Kristiina Kurg
  9. Eva-Maria Tombak
  10. Mart Ustav
  11. Nastassia Shtaida
  12. Evgeny Kulesskiy
  13. Eunji Jo
  14. Jaewon Yang
  15. Hilde Lysvand
  16. Kirsti Løseth
  17. Valentyn Oksenych
  18. Per Arne Aas
  19. Tanel Tenson
  20. Astra Vitkauskiene
  21. Marc P. Windisch
  22. Mona Høysæter Fenstad
  23. Svein Arne Nordbø
  24. Mart Ustav
  25. Magnar Bjørås
  26. Denis Kainov

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Abstract

Combination therapies have become a standard for the treatment for HIV and HCV infections. They are advantageous over monotherapies due to better efficacy and reduced toxicity, as well as the ability to prevent the development of resistant viral strains and to treat viral co-infections. Here, we identify several new synergistic combinations against emerging and re-emerging viral infections in vitro . We observed synergistic activity of nelfinavir with investigational drug EIDD-2801 and convalescent serum against SARS-CoV-2 infection in human lung epithelial Calu-3 cells. We also demonstrated synergistic activity of vemurafenib combination with emetine, homoharringtonine, gemcitabine, or obatoclax against echovirus 1 infection in human lung epithelial A549 cells. We also found that combinations of sofosbuvir with brequinar and niclosamide were synergistic against HCV infection in hepatocyte derived Huh-7.5 cells, whereas combinations of monensin with lamivudine and tenofovir were synergistic against HIV-1 infection in human cervical TZM-bl cells. Finally, we present an online resource that summarizes novel and known antiviral drug combinations and their developmental status. Overall, the development of combinational therapies could have a global impact improving the preparedness and protection of the general population from emerging and re-emerging viral threats.

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  1. ScreenIT

    SciScore for 10.1101/2020.09.17.299933: (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

    Experimental Models: Cell Lines
    SentencesResources
    TZM-bl, previously designated JC53-bl (clone 13) is a human cervical cancer HeLa cell line, stably expressing the firefly luciferase under control of the HIV-1 LTR promoter.
    HeLa
    suggested: CLS Cat# 300194/p772_HeLa, RRID:CVCL_0030)
    TZM-bl cells were grown in DMEM supplemented with 10% FBS and Pen/Strep.
    TZM-bl
    suggested: None
    For the production of HIV-1, 6 × 106 ACH-2 cells were seeded in 10 mL medium.
    ACH-2
    suggested: NIH-ARP Cat# 349-443, RRID:CVCL_0138)
    Briefly, Huh-7.5 cells transiently transfected with HCV RNA transcripts of a cell culture-adapted JFH1 genome expressing NS5A-GFP fusion protein (JFH1_5 A/5B_GFP).
    Huh-7.5
    suggested: RRID:CVCL_7927)
    The Vero-E6 cells were overplayed with VGM containing mixture of the virus and convalescent serum.
    Vero-E6
    suggested: None
    Gene Expression Analysis: A549 cells were treated with 10 μM vemurafenib or vehicle at indicated concentrations.
    A549
    suggested: None
    Software and Algorithms
    SentencesResources
    The half-maximal cytotoxic concentration (CC50) for each compound was calculated based on viability/death curves obtained on mock-infected cells after nonlinear regression analysis with a variable slope using GraphPad Prism software version 7.0a (
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad Software, San Diego, CA, USA).
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    The expected responses were calculated based on the ZIP reference model using SynergyFinder version 2 [13, 14].
    SynergyFinder
    suggested: (SynergyFinder, RRID:SCR_019318)
    Raw microarray data were normalized using the BeadArray, and Limma packages from Bioconductor suite for R.
    BeadArray
    suggested: (beadarray, RRID:SCR_001314)
    Bioconductor
    suggested: (Bioconductor, RRID:SCR_006442)
    Genes differentially expressed between samples and controls were determined using the Limma package.
    Limma
    suggested: (LIMMA, RRID:SCR_010943)
    MassLynx 4.1 software was used for data acquisition, data handling, and instrument control.
    MassLynx
    suggested: (MassLynx , RRID:SCR_014271)
    The heatmap was generated using the pheatmap package (https://cran.rproject.org/web/packages/pheatmap/index.html) based on log-transformed profiling data.
    pheatmap
    suggested: (pheatmap, RRID:SCR_016418)
    In this pathway analysis tool, the pathway data are derived from KEGG database (www.genome.jp/kegg/) 2.11.
    KEGG
    suggested: (KEGG, RRID:SCR_012773)
    The information for the database was obtained from PubMed, clinicaltrials.gov, DrugBank, DrugCentral, the 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)
    DrugCentral
    suggested: (DrugCentral, RRID:SCR_015663)

    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
    NCT04291729CompletedEvaluation of Ganovo （Danoprevir ） Combined With Ritonavir i…
    NCT03111108CompletedEfficacy and Safety of Elbasvir (MK-8742) + Grazoprevir (MK-…
    NCT01045278CompletedHepatitis C in a Cohort of Patients With Maintenance Therapy…
    NCT00255034TerminatedEffects of 48 Weeks Versus 24 Weeks of Therapy With Peg-Intr…
    NCT02480166CompletedComparative Efficacy of Fixed-dose Combination Sofosbuvir + …
    NCT00383864CompletedPegylated Interferon and Ribavirin in Hepatitis C Virus Infe…
    NCT01023217CompletedEntecavir Plus Adefovir in Lamivudine-Resistant Chronic Hepa…
    NCT00922207CompletedA Study of PEGASYS (Peginterferon Alfa-2a (40KD)) in Combina…
    NCT02360592CompletedCombination Therapy With Interferon Plus Interleukin 2 and H…

    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.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2020.09.17.299933v1 on bioRxiv