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iScience . Deciphering COVID-19 host transcriptomic complexity and variations for therapeutic discovery against new variants

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  • iScience . Deciphering COVID-19 host transcriptomic complexity and variations for therapeutic discovery against new variants


    iScience


    . 2022 Sep 3;105068.
    doi: 10.1016/j.isci.2022.105068. Online ahead of print.
    Deciphering COVID-19 host transcriptomic complexity and variations for therapeutic discovery against new variants


    Jing Xing 1 , Rama Shankar 1 , Meehyun Ko 2 , Keke Zhang 3 , Sulin Zhang 3 , Aleksandra Drelich 4 , Shreya Paithankar 1 , Eugene Chekalin 1 , Mei-Sze Chua 5 , Surender Rajasekaran 1 6 , Chien-Te Kent Tseng 4 7 , Mingyue Zheng 3 , Seungtaek Kim 2 , Bin Chen 1 8 9



    Affiliations

    Abstract

    The molecular manifestations of host cells responding to SARS-CoV-2 and its evolving variants infection are vastly different across studying models and conditions, imposing challenges for host-based antiviral drug discovery. Based on the postulation that antiviral drugs tend to reverse the global host gene expression induced by viral infection, we retrospectively evaluated hundreds of signatures derived from 1700 published host transcriptomic profiles of SARS/MERS/SARS-CoV-2 infection using an iterative data-driven approach. A few of these signatures could be reversed by known anti-SARS-CoV-2 inhibitors, suggesting the potential of extrapolating the biology for new variant research. We discovered IMD-0354 as a promising candidate to reverse the signatures globally with nanomolar IC50 against SARS-CoV-2 and its five variants. IMD-0354 stimulated type I interferon antiviral response, inhibited viral entry, and down-regulated hijacked proteins. This study demonstrates that the conserved coronavirus signatures and the transcriptomic reversal approach that leverages polypharmacological effects could guide new variant therapeutic discovery.

    Keywords: SARS-CoV-2; host response; systems medicine; transcriptomic signatures.

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