Tyrosine Kinase Inhibitor Family of Drugs as Prospective Targeted Therapy for COVID-19 Based on In Silico And 3D-Human Vascular Lung Model Studies

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COVID-19 pandemic has ravaged the world and vaccines have been rapidly developed as preventive measures. But there is no target-based therapy which can be used if infection sets in. Remdesiver and dexamethasone were not designed to combat COVID-19 but are used clinically till better targeted therapies are available. Given this situation target based therapies that intervene in the disease pathway are urgently needed.

Since COVID-19 genesis is driven by uncontrolled inflammation/thrombosis and protein kinases are critical in mounting this response, we explored if available tyrosine kinase inhibitors (TKI’s) can be used as intervention. We profiled four TKI’s namely; Lapatinib, Dasatinib, Pazopanib and Sitravatinib which inhibit tyrosine kinases but are completely distinct in their chemical structures.

We demonstrate using in silico and an in vitro 3D-human vascular lung model which profiles anti-inflammatory and anti-thrombogenic properties that all four TKI’s are active in varying degrees. Our findings that chemically different TKI’s which share kinase inhibition as the common mechanism of action are active, strongly indicates that it’s a tyrosine kinase target-based activity and not off-target arbitrary effect. We propose that TKI’s, approved for human use and widely available, can be rapidly deployed as specific target-based therapy for COVID-19.

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  1. SciScore for 10.1101/2021.05.13.443955: (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

    Samples were added to the microplate pre-coated with human IL-1β antibody which captures the IL-1 β present in the samples.
    suggested: None
    A secondary anti-human IL-1β antibody conjugated to biotin was added to the plate.
    anti-human IL-1β
    suggested: None
    Software and Algorithms
    2.1 Ligand preparation: The 2D structures of tyrosine kinase drugs were downloaded from Drugbank database [2] and prepared using Flare software.
    suggested: (DrugBank, RRID:SCR_002700)

    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:

    NCT03680521Active, not recruitingNeoadjuvant Sitravatinib in Combination With Nivolumab in Pa…

    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.

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