Fang Chao, Mei Jie, Tian Huixiang, Liou Yu-Ligh, Rong Dingchao, Zhang Wei, Liao Qianjin, Wu Nayiyuan
Hunan Key Laboratory of Pharmacogenetics, Department of Clinical Pharmacology, Xiangya Hospital, Institute of Clinical Pharmacology, Central South University, Changsha, China.
Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
Front Physiol. 2021 Jan 22;11:605792. doi: 10.3389/fphys.2020.605792. eCollection 2020.
Coronavirus Disease 2019 (COVID-19) is an acute respiratory infectious disease that appeared at the end of 2019. As of July 2020, the cumulative number of infections and deaths have exceeded 15 million and 630,000, respectively. And new cases are increasing. There are still many difficulties surrounding research on the mechanism and development of therapeutic vaccines. It is urgent to explore the pathogenic mechanism of viruses to help prevent and treat COVID-19. In our study, we downloaded two datasets related to COVID-19 (GSE150819 and GSE147507). By analyzing the high-throughput expression matrix of uninfected human bronchial organoids and infected human bronchial organoids in the GSE150819, 456 differentially expressed genes (DEGs) were identified, which were mainly enriched in the cytokine-cytokine receptor interaction pathway and so on. We also constructed the protein-protein interaction (PPI) network of DEGs to identify the hub genes. Then we analyzed GSE147507, which contained lung adenocarcinoma cell lines (A549 and Calu3) and the primary bronchial epithelial cell line (NHBE), obtaining 799, 460, and 46 DEGs, respectively. The results showed that in human bronchial organoids, A549, Calu3, and NHBE samples infected with SARS-CoV-2, only one upregulated gene CSF3 was identified. Interestingly, CSF3 is one of the hub genes we previously screened in GSE150819, suggesting that CSF3 may be a potential drug target. Further, we screened potential drugs targeting CSF3 by MOE; the top 50 drugs were screened by flexible docking and rigid docking, with 37 intersections. Two antiviral drugs (Elbasvir and Ritonavir) were included; Elbasvir and Ritonavir formed van der Waals (VDW) interactions with surrounding residues to bind with CSF3, and Elbasvir and Ritonavir significantly inhibited CSF3 protein expression.
2019冠状病毒病（COVID-19）是一种于2019年末出现的急性呼吸道传染病。截至2020年7月，累计感染病例数和死亡病例数分别超过1500万和63万，且新病例仍在增加。围绕治疗性疫苗的作用机制和研发仍存在诸多困难。探索病毒的致病机制以帮助预防和治疗COVID-19迫在眉睫。在我们的研究中，我们下载了两个与COVID-19相关的数据集（GSE150819和GSE147507）。通过分析GSE150819中未感染的人支气管类器官和感染的人支气管类器官的高通量表达矩阵，鉴定出456个差异表达基因（DEG），这些基因主要富集在细胞因子-细胞因子受体相互作用途径等中。我们还构建了DEG的蛋白质-蛋白质相互作用（PPI）网络以鉴定枢纽基因。然后我们分析了GSE147507，其包含肺腺癌细胞系（A549和Calu3）和原代支气管上皮细胞系（NHBE），分别获得了799、460和46个DEG。结果表明，在感染严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的人支气管类器官、A549、Calu3和NHBE样本中，仅鉴定出一个上调基因集落刺激因子3（CSF3）。有趣的是，CSF3是我们先前在GSE150819中筛选出的枢纽基因之一，这表明CSF3可能是一个潜在的药物靶点。此外，我们通过分子操作环境（MOE）筛选了靶向CSF3的潜在药物；通过柔性对接和刚性对接筛选出前50种药物，其中有37个交集。其中包括两种抗病毒药物（艾尔巴韦和利托那韦）；艾尔巴韦和利托那韦与周围残基形成范德华（VDW）相互作用以与CSF3结合，且艾尔巴韦和利托那韦显著抑制CSF3蛋白表达。
