Enhancement of the IFN-β-induced host signature informs repurposed drugs for COVID-19

Chen-Tsung Huang; Tai-Ling Chao; Han-Chieh Kao; Yu-Hao Pang; Wen-Hau Lee; Chiao-Hui Hsieh; Sui-Yuan Chang; Hsuan-Cheng Huang; Hsueh-Fen Juan

doi:10.1016/j.heliyon.2020.e05646

Enhancement of the IFN-β-induced host signature informs repurposed drugs for COVID-19

Heliyon. 2020 Dec;6(12):e05646. doi: 10.1016/j.heliyon.2020.e05646. Epub 2020 Dec 2.

Authors

Chen-Tsung Huang¹, Tai-Ling Chao², Han-Chieh Kao², Yu-Hao Pang², Wen-Hau Lee², Chiao-Hui Hsieh³, Sui-Yuan Chang^{2

4}, Hsuan-Cheng Huang⁵, Hsueh-Fen Juan^{1

3}

Affiliations

¹ Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 10617, Taiwan.
² Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei 10048, Taiwan.
³ Department of Life Science, National Taiwan University, Taipei 10617, Taiwan.
⁴ Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan.
⁵ Institute of Biomedical Informatics, National Yang-Ming University, Taipei 11221, Taiwan.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a causative agent for the outbreak of coronavirus disease 2019 (COVID-19). This global pandemic is now calling for efforts to develop more effective COVID-19 therapies. Here we use a host-directed approach, which focuses on cellular responses to diverse small-molecule treatments, to identify potentially effective drugs for COVID-19. This framework looks at the ability of compounds to elicit a similar transcriptional response to IFN-β, a type I interferon that fails to be induced at notable levels in response to SARS-CoV-2 infection. By correlating the perturbation profiles of ~3,000 small molecules with a high-quality signature of IFN-β-responsive genes in primary normal human bronchial epithelial cells, our analysis revealed four candidate COVID-19 compounds, namely homoharringtonine, narciclasine, anisomycin, and emetine. We experimentally confirmed that the predicted compounds significantly inhibited SARS-CoV-2 replication in Vero E6 cells at nanomolar, relatively non-toxic concentrations, with half-maximal inhibitory concentrations of 165.7 nM, 16.5 nM, and 31.4 nM for homoharringtonine, narciclasine, and anisomycin, respectively. Together, our results corroborate a host-centric strategy to inform protective antiviral therapies for COVID-19.

Keywords: Bioinformatics; COVID-19; Drug repurposing; Host-directed therapy; Infectious disease; Pharmaceutical science; Systems biology; Transcriptomics; Type I interferon.