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

ABSTRACT: The molecular manifestations of host cells responding to SARS-CoV-2 and its evolving variants of infection are vastly different across the studied 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 1,700 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.

SUBMITTER: Xing J

PROVIDER: S-EPMC9439871 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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

Xing Jing J Shankar Rama R Ko Meehyun M Zhang Keke K Zhang Sulin S Drelich Aleksandra A Paithankar Shreya S Chekalin Eugene E Chua Mei-Sze MS Rajasekaran Surender S Kent Tseng Chien-Te CT Zheng Mingyue M Kim Seungtaek S Chen Bin B

iScience 20220903 10

The molecular manifestations of host cells responding to SARS-CoV-2 and its evolving variants of infection are vastly different across the studied 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 1,700 published host transcriptomic profiles of SARS/MERS/SARS-CoV-2 infection usi ...[more]

PMID: 36093376

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Dataset Information

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

Publications

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

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