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Macrolides May Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Entry into Cells: A Quantitative Structure Activity Relationship Study and Experimental Validation

  • Jorge Galvez*
    Jorge Galvez
    Molecular Topology and Drug Design Unit, Department of Physical Chemistry, Universitat de Valencia, Burjassot 46100, Spain
    *Email: [email protected]. Tel.: +34-963544891.
    More by Jorge Galvez
  • Riccardo Zanni
    Riccardo Zanni
    Molecular Topology and Drug Design Unit, Department of Physical Chemistry, Universitat de Valencia, Burjassot 46100, Spain
  • Maria Galvez-Llompart
    Maria Galvez-Llompart
    Molecular Topology and Drug Design Unit, Department of Physical Chemistry, Universitat de Valencia, Burjassot 46100, Spain
    Instituto de Tecnología Química, UPV-CSIC, Universidad Politícnica de Valencia, Valencia 46022, Spain
  • , and 
  • Jose Maria Benlloch
    Jose Maria Benlloch
    Instituto de Instrumentación para Imagen Molecular, Centro Mixto CSIC—Universitat Politècnica de València, Valencia 46022, Spain
Cite this: J. Chem. Inf. Model. 2021, 61, 4, 2016–2025
Publication Date (Web):March 18, 2021
https://doi.org/10.1021/acs.jcim.0c01394
Copyright © 2021 American Chemical Society

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    Abstract

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    The global pandemic caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is threatening the health and economic systems worldwide. Despite the enormous efforts of scientists and clinicians around the world, there is still no drug or vaccine available worldwide for the treatment and prevention of the infection. A rapid strategy for the identification of new treatments is based on repurposing existing clinically approved drugs that show antiviral activity against SARS-CoV-2 infection. In this study, after developing a quantitative structure activity relationship analysis based on molecular topology, several macrolide antibiotics are identified as promising SARS-CoV-2 spike protein inhibitors. To confirm the in silico results, the best candidates were tested against two human coronaviruses (i.e., 229E-GFP and SARS-CoV-2) in cell culture. Time-of-addition experiments and a surrogate model of viral cell entry were used to identify the steps in the virus life cycle inhibited by the compounds. Infection experiments demonstrated that azithromycin, clarithromycin, and lexithromycin reduce the intracellular accumulation of viral RNA and virus spread as well as prevent virus-induced cell death, by inhibiting the SARS-CoV-2 entry into cells. Even though the three macrolide antibiotics display a narrow antiviral activity window against SARS-CoV-2, it may be of interest to further investigate their effect on the viral spike protein and their potential in combination therapies for the coronavirus disease 19 early stage of infection.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jcim.0c01394.

    • Descriptor values, classification of compounds, and probability of activity for the training set of models 1 and 2 (Tables S1 and S3) and the leave-some-out validation test for DF1–2 (Tables S2 and S4) (PDF)

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