Identification of SGLT2 inhibitor Ertugliflozin as a treatment for COVID-19 using computational and experimental paradigm

  1. Shalini Saxena
  2. Kranti Meher
  3. Madhuri Rotella
  4. Subhramanyam Vangala
  5. Satish Chandran
  6. Nikhil Malhotra
  7. Ratnakar Palakodeti
  8. Sreedhara R Voleti
  9. Uday Saxena

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Abstract

Drug repurposing can expedite the process of drug development by identifying known drugs which are effective against SARS-CoV-2. The RBD domain of SARS-CoV-2 Spike protein is a promising drug target due to its pivotal role in viral-host attachment. These specific structural domains can be targeted with small molecules or drug to disrupt the viral attachment to the host proteins. In this study, FDA approved Drugbank database were screened using a virtual screening approach and computational chemistry methods. Five drugs were short listed for further profiling based on docking score and binding energies. Further these selected drugs were tested for their in vitro biological activity. There was significant correlation between the prediction from computational studies and the actual RBD-ACE2 binding inhibition by the drugs. Then, we performed a series of studies that mimic some of the biological events seen in COVID-19 patients such as secretion of IL1β, presentation of a more thrombogenic endothelium by production of thrombomodulin and accumulation of inflammatory cells such as monocytes in the lungs. Of all the drugs, most promising drug was Ertugliflozin which is used for type-2 diabetes. This drug possesses several desired properties and may be a good candidate for immediate repurposing for treatment of COVID-19.

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    SciScore for 10.1101/2021.06.18.448921: (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

    Antibodies
    SentencesResources
    Following an overnight incubation, microplate was washed six times using wash buffer in order to remove any unbound biotin conjugated anti-human IL-1β antibody.
    anti-human IL-1β
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    After incubation, once the collagen is solidified A549 cells flask which has reached 80-90% confluence were trypsinized and cells were counted with the help of haemocytometer.
    A549
    suggested: None
    After incubation, once the collagen is solidified HUVEC cells flask which has reached 80-90% confluence was trypsinized.
    HUVEC
    suggested: None
    Software and Algorithms
    SentencesResources
    2.1 Ligand preparation: The 2D structures of all the drugs were downloaded from Drugbank database and prepared using Flare software.
    Drugbank
    suggested: (DrugBank, RRID:SCR_002700)
    MTT stained HL60 monocytic cells were added to each well in 96 well plate and incubated the plate for one hour and the wells were then washed twice with the media and pictures were taken of all the wells and the bound HL 60 cells were counted with the help of ImageJ, an open access software platform.
    ImageJ
    suggested: (ImageJ, RRID:SCR_003070)

    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 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.
    • No funding statement was detected.
    • 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.

  2. Version published to 10.1101/2021.06.18.448921v1 on bioRxiv