Department of Microbiology, College of Science & Technology, Dankook University, Cheonan 31116, Korea.
Deargen Inc., Daejeon, Yuseong-gu, Munji-dong 103-6, Korea.
Viruses. 2020 Jul 20;12(7):776. doi: 10.3390/v12070776.
The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects almost everyone in the world in many ways. We previously predicted antivirals (atazanavir, remdesivir and lopinavir/ritonavir) and non-antiviral drugs (tiotropium and rapamycin) that may inhibit the replication complex of SARS-CoV-2 using our molecular transformer-drug target interaction (MT-DTI) deep-learning-based drug-target affinity prediction model. In this study, we dissected molecular pathways upregulated in SARS-CoV-2-infected normal human bronchial epithelial (NHBE) cells by analyzing an RNA-seq data set with various bioinformatics approaches, such as gene ontology, protein-protein interaction-based network and gene set enrichment analyses. The results indicated that the SARS-CoV-2 infection strongly activates TNF and NFκB-signaling pathways through significant upregulation of the , , , , , and genes. In addition to these pathways, lung fibrosis, keratinization/cornification, rheumatoid arthritis, and negative regulation of interferon-gamma production pathways were also significantly upregulated. We observed that these pathologic features of SARS-CoV-2 are similar to those observed in patients with chronic obstructive pulmonary disease (COPD). Intriguingly, tiotropium, as predicted by MT-DTI, is currently used as a therapeutic intervention in COPD patients. Treatment with tiotropium has been shown to improve pulmonary function by alleviating airway inflammation. Accordingly, a literature search summarized that tiotropium reduced expressions of , , , and TNF in vitro or in vivo, and many of them have been known to be deregulated in COPD patients. These results suggest that COVID-19 is similar to an acute mode of COPD caused by the SARS-CoV-2 infection, and therefore tiotropium may be effective for COVID-19 patients.
新型冠状病毒病 2019（COVID-19）是由严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）引起的，以多种方式影响着世界上几乎每个人。我们之前使用我们基于分子变换-药物靶标相互作用（MT-DTI）的深度学习药物靶标亲和力预测模型，预测了可能抑制 SARS-CoV-2 复制复合物的抗病毒药物（阿扎那韦、瑞德西韦和洛匹那韦/利托那韦）和非抗病毒药物（噻托溴铵和雷帕霉素）。在这项研究中，我们通过使用各种生物信息学方法（如基因本体论、蛋白质-蛋白质相互作用网络和基因集富集分析）分析 RNA-seq 数据集，剖析了 SARS-CoV-2 感染正常人类支气管上皮（NHBE）细胞上调的分子途径。结果表明，SARS-CoV-2 感染通过显著上调 、 、 、 、 和 基因强烈激活 TNF 和 NFκB 信号通路。除了这些途径外，肺纤维化、角质化/角化、类风湿关节炎和干扰素-γ产生的负调控途径也显著上调。我们观察到，SARS-CoV-2 的这些病理特征与慢性阻塞性肺疾病（COPD）患者观察到的特征相似。有趣的是，MT-DTI 预测的噻托溴铵目前被用作 COPD 患者的治疗干预措施。噻托溴铵的治疗已被证明通过减轻气道炎症来改善肺功能。因此，文献检索总结了噻托溴铵在体外或体内降低 、 、 、TNF 的表达，其中许多已被证明在 COPD 患者中失调。这些结果表明，COVID-19 类似于由 SARS-CoV-2 感染引起的 COPD 的急性模式，因此噻托溴铵可能对 COVID-19 患者有效。
