Immune-Modulating Drug MP1032 with SARS-CoV-2 Antiviral Activity In Vitro: A potential Multi-Target Approach for Prevention and Early Intervention Treatment of COVID-19

  1. Sara Schumann
  2. Astrid Kaiser
  3. Ferdinando Nicoletti
  4. Katia Mangano
  5. Paolo Fagone
  6. Eduard van Wijk
  7. Yu Yan
  8. Petra Schulz
  9. Beate Ludescher
  10. Michael Niedermaier
  11. Joerg von Wegerer
  12. Pia Rauch
  13. Christian Setz
  14. Ulrich Schubert
  15. Wolfgang Brysch

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Abstract

At least since March 2020, the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic and the multi-organ coronavirus disease 2019 (COVID-19) are keeping a firm grip on the world. Although most cases are mild, older patients and those with co-morbidities are at increased risk of developing a cytokine storm, characterized by a systemic inflammatory response leading to acute respiratory distress syndrome and organ failure. The present paper focuses on the small molecule MP1032, describes its mode of action, and gives rationale why it is a promising option for the prevention/treatment of the SARS-CoV-2-induced cytokine storm. MP1032 is a phase-pure anhydrous polymorph of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt that exhibits good stability and bioavailability. The physiological action of MP1032 is based on a multi-target mechanism including localized, self-limiting reactive oxygen species (ROS) scavenging activities that were demonstrated in a model of lipopolysaccharide (LPS)-induced joint inflammation. Furthermore, its immune-regulatory and PARP-1-modulating properties, coupled with antiviral effects against SARS-CoV-2, have been demonstrated in various cell models. Preclinical efficacy was elucidated in LPS-induced endotoxemia, a model with heightened innate immune responses that shares many similarities to COVID-19. So far, during oral clinical development with three-month daily administrations, no serious adverse drug reactions occurred, highlighting the outstanding safety profile of MP1032.

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    SciScore for 10.1101/2020.11.03.20216580: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomization4.2 In vitro studies: 4.3 In vivo studies: 4.4 Clinical phase II trial: In a randomized, double-blind, placebo-controlled study, two oral doses of MP1032 were evaluated over a period of 12 weeks in patients with moderate to severe chronic plaque psoriasis (PASI 10–20).
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    The SARS-CoV-2 Nucleocapsid antibody (Genetex, GTX135357) and the anti-rabbit secondary antibody coupled to horseradish peroxidase (Dianova, Germany) were used.
    GTX135357
    suggested: (GeneTex Cat# GTX135357, RRID:AB_2868464)
    anti-rabbit
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    PARP-1 activity in HL-60 cells: PARP-1 activity in human HL-60 cells was determined using the PARP in vivo Pharmacodynamic Assay II (Trevigen, USA) according to the manufacturer’s instructions.
    HL-60
    suggested: None
    Software and Algorithms
    SentencesResources
    Statistical calculation was performed using GraphPad Prism (GraphPad Software, La Jolla, USA).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    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: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04344184RecruitingSAFEty Study of Early Infusion of Vitamin C for Treatment of…
    NCT04323514RecruitingUse of Ascorbic Acid in Patients With COVID 19
    NCT04374461RecruitingA Study of N-acetylcysteine in Patients With COVID-19 Infect…
    NCT04419025RecruitingEfficacy of N-Acetylcysteine (NAC) in Preventing COVID-19 Fr…

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    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

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  2. Version published to 10.3390/ijms21228803
  3. Version published to 10.1101/2020.11.03.20216580v1 on medRxiv