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    Pyrimidine inhibitors synergize with nucleoside analogues to block SARS-CoV-2.

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    Author
    Schultz, David C
    Johnson, Robert M
    Ayyanathan, Kasirajan
    Miller, Jesse
    Whig, Kanupriya
    Kamalia, Brinda
    Dittmar, Mark
    Weston, Stuart
    Hammond, Holly L
    Dillen, Carly
    Ardanuy, Jeremy
    Taylor, Louis
    Lee, Jae Seung
    Li, Minghua
    Lee, Emily
    Shoffler, Clarissa
    Petucci, Christopher
    Constant, Samuel
    Ferrer, Marc
    Thaiss, Christoph A
    Frieman, Matthew B
    Cherry, Sara
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    Date
    2022-02-07
    Journal
    Nature
    Publisher
    Springer Nature
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1038/s41586-022-04482-x
    Abstract
    The SARS-CoV-2 virus has infected more than 261 million people and led to more than 5 million deaths in the last year and a half1 (WHO.org). SARS-CoV-2-infected individuals typically develop mild to severe flu-like symptoms, while infection of a subset of individuals leads to severe to fatal clinical outcomes2. While vaccines have been rapidly developed to combat SARS-CoV-2, there has been a dearth of antiviral therapeutics. There is an urgent need for therapeutics which has been amplified by the emerging threats of variants that may evade vaccines. Large-scale efforts are underway to identify antiviral drugs and we screened ~18,000 drugs for antiviral activity using live virus infection in human respiratory cells and validate 122 drugs with antiviral activity and selectivity against SARS-CoV-2. Amongst these candidates are 16 nucleoside analogues, the largest category of clinically used antivirals. This included the antivirals remdesivir and molnupiravir, which have been approved for use in COVID-19. RNA viruses rely on a high supply of nucleoside triphosphates from the host to efficiently replicate, and we identified a panel of host nucleoside biosynthesis inhibitors as antiviral. Moreover, we found that combining pyrimidine biosynthesis inhibitors with antiviral nucleoside analogues synergistically inhibits SARS-CoV-2 infection in vitro and in vivo against emerging strains of SARS-CoV-2 suggesting a clinical path forward.
    Rights/Terms
    © 2022. The Author(s), under exclusive licence to Springer Nature Limited.
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/18100
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41586-022-04482-x
    Scopus Count
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    UMB Coronavirus Publications
    UMB Open Access Articles

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