Deciphering COVID-19 host transcriptomic complexity and variations for therapeutic discovery against new variants.
Deciphering COVID-19 host transcriptomic complexity and variations for therapeutic discovery against new variants.
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DOI：
10.1016/j.isci.2022.105068
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发表时间：
2022-10-21
期刊：
影响因子：
5.8
通讯作者：
Chen, Bin
中科院分区：
文献类型：
--
作者：
Xing, Jing;Shankar, Rama;Ko, Meehyun;Zhang, Keke;Zhang, Sulin;Drelich, Aleksandra;Paithankar, Shreya;Chekalin, Eugene;Chua, Mei-Sze;Rajasekaran, Surender;Tseng, Chien-Te Kent;Zheng, Mingyue;Kim, Seungtaek;Chen, Bin
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. Robust coronavirus infection signatures were identified from 1,700 host profiles The signatures captured essential pathogenic biology of SARS-CoV-2 and its variants IMD-0354 reversed these signatures and inhibited new variants with nM IC50s The antiviral potential of IMD-0354 benefits from its polypharmacological effects Microbiology; Virology; Bioinformatics; Omics; Transcriptomics.
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