Probenecid inhibits SARS-CoV-2 replication in vivo and in vitro

  1. Jackelyn Murray
  2. Robert J. Hogan
  3. David E. Martin
  4. Kathy Blahunka
  5. Fred D. Sancilio
  6. Rajiv Balyan
  7. Mark Lovern
  8. Richard Still
  9. Ralph A. Tripp

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Abstract

Effective vaccines are slowing the COVID-19 pandemic, but SARS-CoV-2 will likely remain an issue in the future making it important to have therapeutics to treat patients. There are few options for treating patients with COVID-19. We show probenecid potently blocks SARS-CoV-2 replication in mammalian cells and virus replication in a hamster model. Furthermore, we demonstrate that plasma concentrations up to 50-fold higher than the protein binding adjusted IC 90 value are achievable for 24 h following a single oral dose. These data support the potential clinical utility of probenecid to control SARS-CoV-2 infection in humans.

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  1. Version published to 10.1038/s41598-021-97658-w
  2. ScreenIT

    SciScore for 10.1101/2021.05.21.445119: (What is this?)

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

    Table 1: Rigor

    EthicsIACUC: The hamster study received ethical approval from the University of Georgia IACUC committee and was performed by certified staff in an Association for Assessment and Accreditation of Laboratory Animal Care International-accredited facility.
    Field Sample Permit: Virus and cells: SARS-CoV-2 isolate nCoV-WA1-2020 (MN985325.1) or the variant (hCoV-19/USA/CA_CDC_5574/2020, B.1.1.7; GenBank: MW422255.1) were received from BEI Resources managed under contract by American Type Culture Collection (ATCC).
    Sex as a biological variableIn this study, five adult healthy male subjects (20-39 years, 53-86 kg) were given oral 500, 1000, and 2000 mg probenecid at least one week apart and blood was collected until 48h.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    SARS-CoV-2 In Vitro Assay: Vero E6 cells (ATCC CRL-1586) were plated in 12-well plates at 5 x 105 cells/well and incubated overnight at 37°C.
    Vero E6
    suggested: None
    Software and Algorithms
    SentencesResources
    These data were fit in a nonlinear mixed-effects framework using Phoenix NLME software34.
    Phoenix NLME
    suggested: None

    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: We detected the following sentences addressing limitations in the study:
    Other compounds that interact with OAT3 include the antiviral drugs oseltamivir phosphate (Tamiflu) and acyclovir10, as well as angiotensin II receptor blockers30, however, their interaction is weak and their pharmacological actions confer safety and tolerability limitations that preclude their use in drug repurposing.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    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.

    Results from scite Reference Check: We found no unreliable references.

    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.

  3. Version published to 10.1101/2021.05.21.445119v1 on bioRxiv