Stenoparib, an inhibitor of cellular poly (ADP-ribose) polymerase (PARP), blocks replication of the SARS-CoV-2 human coronavirus in vitro

  1. Nathan E. Stone
  2. Sierra A. Jaramillo
  3. Ashley N. Jones
  4. Adam J. Vazquez
  5. Madison Martz
  6. Lora M. Versluis
  7. Marlee O. Raniere
  8. Haley E. Nunnally
  9. Katherine E. Zarn
  10. Roxanne Nottingham
  11. Jason W. Sahl
  12. David M. Wagner
  13. Steen Knudsen
  14. Erik W. Settles
  15. Paul S. Keim
  16. Christopher T. French

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Abstract

By late 2020, the coronavirus disease (COVID-19) pandemic, caused by SARS-CoV-2 has caused tens of millions of infections and over 1 million deaths worldwide. A protective vaccine and more effective therapeutics are urgently needed. We evaluated a new PARP inhibitor, stenoparib, which was recently advanced to Stage II clinical trials for treatment of ovarian cancer, for activity against human respiratory coronaviruses, including SARS-CoV-2, in vitro . Stenoparib exhibits dose-dependent suppression of SARS-CoV-2 multiplication and spread in Vero E6 monkey kidney and Calu-3 human lung adenocarcinoma cells. Stenoparib was also strongly inhibitory to the HCoV-NL63 human seasonal respiratory coronavirus. Compared to remdesivir, which inhibits viral replication downstream of cell entry, stenoparib impedes entry and post-entry processes as determined by time-of-addition (TOA) experiments. Moreover, a 10 μM dosage of stenoparib – below the approximated 25.5 μM half-maximally effective concentration (EC 50 ), combined with 0.5 μM remdesivir suppressed coronavirus growth by more than 90%, indicating a potentially synergistic effect for this drug combination. Stenoparib as a standalone or as part of combinatorial therapy with remdesivir should be a valuable addition to the arsenal against COVID-19.

Importance

New therapeutics are urgently needed in the fight against COVID-19. Repurposing drugs that are either already approved for human use or are in advanced stages of the approval process can facilitate more rapid advances toward this goal. The PARP inhibitor stenoparib may be such a drug, as it is currently in Stage II clinical trials for the treatment of ovarian cancer and its safety and dosage in humans has already been established. Our results indicate that stenoparib possesses strong antiviral activity against SARS-CoV-2 and other coronaviruses in vitro. This activity appears to be based on multiple modes of action, where both pre-entry and post-entry viral replication processes are impeded. This may provide a therapeutic advantage over many current options that have a narrower target range. Moreover, our results suggest that stenoparib and remdesivir in combination may be especially potent against coronavirus infection.

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  1. ScreenIT

    SciScore for 10.1101/2020.11.12.380394: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    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
    We used Vero E6 (ATCC CRL-1586) and Calu-3 cells (ATCC HTB-55) from the American Type Culture Collection (ATCC, Manassas, VA, USA) in EMEM (Eagle’s Minimum Essential Medium) supplemented with 2% or 10% fetal bovine serum (FBS), 100 U/mL penicillin, 100 μg/mL streptomycin ‘pen-strep’, 0.01 M HEPES, 1 mM sodium pyruvate, 1x non-essential amino acids solution (SH3023801, Thermo Fisher), and 2 mM L-glutamine, for the propagation and experimentation with SARS-CoV-2.
    Vero E6
    suggested: None
    LLC-MK2 cells (ATCC CCL-7), maintained in Medium 199 (M4530, Millipore Sigma) supplemented with FBS and pen-strep, were used for the experiments with the NL63 coronavirus.
    LLC-MK2
    suggested: None
    Calu-3 cells were incubated for >10 days to achieve 80-90% confluency.
    Calu-3
    suggested: None
    Software and Algorithms
    SentencesResources
    Values were plotted using GraphPad Prism version 8.0.0 for Windows (GraphPad Software) and annotated using Adobe Illustrator (Adobe Systems Incorporated).
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Adobe Illustrator
    suggested: (Adobe Illustrator, RRID:SCR_010279)
    For NL63, the reference genome (NC_005831) was divided into 200 nucleotide fragments, which were aligned against a set of 2,771 coronavirus genomes with BLAT v36.2 (52) in conjunction with LS-BSR v1.2.2 (53).
    BLAT
    suggested: (BLAT, RRID:SCR_011919)
    LS-BSR
    suggested: None
    A probe was designed targeting the spike (S) protein furin cleavage site with Primer3.
    Primer3
    suggested: (Primer3, RRID:SCR_003139)
    Statistical significance was determined using a parametric unpaired t-test in GraphPad Prism version 8.0.0.
    GraphPad Prism
    suggested: (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.

    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 10.1101/2020.11.12.380394 on bioRxiv