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    The SKI complex is a broad-spectrum, host-directed antiviral drug target for coronaviruses, influenza, and filoviruses.

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    Author
    Weston, Stuart
    Baracco, Lauren
    Keller, Chloe
    Matthews, Krystal
    McGrath, Marisa E
    Logue, James
    Liang, Janie
    Dyall, Julie
    Holbrook, Michael R
    Hensley, Lisa E
    Jahrling, Peter B
    Yu, Wenbo
    MacKerell, Alexander D
    Frieman, Matthew B
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    Date
    2020-11-12
    Journal
    Proceedings of the National Academy of Sciences of the United States of America
    Publisher
    National Academy of Sciences
    Type
    Article
    Other
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1073/pnas.2012939117
    Abstract
    The SARS-CoV-2 pandemic has made it clear that we have a desperate need for antivirals. We present work that the mammalian SKI complex is a broad-spectrum, host-directed, antiviral drug target. Yeast suppressor screening was utilized to find a functional genetic interaction between proteins from influenza A virus (IAV) and Middle East respiratory syndrome coronavirus (MERS-CoV) with eukaryotic proteins that may be potential host factors involved in replication. This screening identified the SKI complex as a potential host factor for both viruses. In mammalian systems siRNA-mediated knockdown of SKI genes inhibited replication of IAV and MERS-CoV. In silico modeling and database screening identified a binding pocket on the SKI complex and compounds predicted to bind. Experimental assays of those compounds identified three chemical structures that were antiviral against IAV and MERS-CoV along with the filoviruses Ebola and Marburg and two further coronaviruses, SARS-CoV and SARS-CoV-2. The mechanism of antiviral activity is through inhibition of viral RNA production. This work defines the mammalian SKI complex as a broad-spectrum antiviral drug target and identifies lead compounds for further development.
    Keyword
    antiviral host factor
    broad-spectrum antiviral
    coronavirus
    filovirus
    influenza
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/14255
    ae974a485f413a2113503eed53cd6c53
    10.1073/pnas.2012939117
    Scopus Count
    Collections
    UMB Coronavirus Publications
    UMB Open Access Articles 2020

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