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

ABSTRACT: COVID-19 has infected 244 million people globally and evolved several variants with higher infectivity. Drug repurposing could be an efficient and timely means of drug discovery for the pandemic. To date, more than two hundred repurposed SARS-CoV-2 inhibitors have been reported but with moderate efficacy or acute toxicity. Thus, there is a great need to find new effective candidates against SARS-CoV-2, especially the new variants, with good safety profiles. We analyzed 17 hundred published host RNA-seq samples of SARS/MERS/SARS-CoV-2 infection derived from pre-clinical models or patients, together with the reported coronavirus inhibitors to summarize a robust coronavirus-induced host gene expression change signature, which captured biological processes involved in host cell machinery hijacking and immune evasion. Then we searched for drugs potently reversing the infection signature and discovered IMD-0354 as a promising candidate with nanomolar IC50 against SARS-CoV-2 and 6 variants, showing a wide therapeutic window of more than 100-fold. The RNA-seq of IMD-0354 treated cells infected with SARS-CoV-2 reaved that this drug could stimulate type I interferon antiviral response, inhibit viral entry and down-regulate hijacked proteins. This work demonstrated the power of biological big data and the efficiency of a system-based drug discovery approach, which can be used in future pandemic.

ORGANISM(S): Homo sapiens

PROVIDER: GSE187420 | GEO | 2022/02/28

REPOSITORIES: GEO

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