Huang Chen-Tsung, Chao Tai-Ling, Kao Han-Chieh, Pang Yu-Hao, Lee Wen-Hau, Hsieh Chiao-Hui, Chang Sui-Yuan, Huang Hsuan-Cheng, Juan Hsueh-Fen
Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 10617, Taiwan.
Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei 10048, Taiwan.
Heliyon. 2020 Dec;6(12):e05646. doi: 10.1016/j.heliyon.2020.e05646. Epub 2020 Dec 2.
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.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是2019冠状病毒病（COVID-19）疫情的病原体。这场全球大流行现在需要努力开发更有效的COVID-19治疗方法。在这里，我们采用一种以宿主为导向的方法，该方法专注于细胞对多种小分子治疗的反应，以确定可能对COVID-19有效的药物。这个框架研究化合物引发与IFN-β类似转录反应的能力，IFN-β是一种I型干扰素，在对SARS-CoV-2感染的反应中未能在显著水平上被诱导。通过将约3000种小分子的扰动谱与原代正常人支气管上皮细胞中IFN-β反应基因的高质量特征相关联，我们的分析揭示了四种候选COVID-19化合物，即高三尖杉酯碱、水仙碱、茴香霉素和吐根碱。我们通过实验证实，预测的化合物在纳摩尔浓度下能显著抑制Vero E6细胞中的SARS-CoV-2复制，且相对无毒，高三尖杉酯碱、水仙碱和茴香霉素的半数最大抑制浓度分别为165.7 nM、16.5 nM和31.4 nM。总之，我们的结果证实了一种以宿主为中心的策略，为COVID-19的保护性抗病毒治疗提供依据。
