Wang Zhihan, Guo Kai, Gao Pan, Pu Qinqin, Li Changlong, Hur Junguk, Wu Min
Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58202, USA.
Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
Precis Clin Med. 2021 Aug 28;4(4):215-230. doi: 10.1093/pcmedi/pbab022. eCollection 2021 Dec.
Coronavirus disease 2019 (COVID-19) has impacted almost every part of human life worldwide, posing a massive threat to human health. The lack of time for new drug discovery and the urgent need for rapid disease control to reduce mortality have led to a search for quick and effective alternatives to novel therapeutics, for example drug repurposing. To identify potentially repurposable drugs, we employed a systematic approach to mine candidates from U.S. FDA-approved drugs and preclinical small-molecule compounds by integrating gene expression perturbation data for chemicals from the Library of Integrated Network-Based Cellular Signatures project with a publicly available single-cell RNA sequencing dataset from patients with mild and severe COVID-19 (GEO: GSE145926, public data available and accessed on 22 April 2020). We identified 281 FDA-approved drugs that have the potential to be effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, 16 of which are currently undergoing clinical trials to evaluate their efficacy against COVID-19. We experimentally tested and demonstrated the inhibitory effects of tyrphostin-AG-1478 and brefeldin-a, two chemical inhibitors of glycosylation (a post-translational modification) on the replication of the single-stranded ribonucleic acid (ssRNA) virus influenza A virus as well as on the transcription and translation of host cell cytokines and their regulators (IFNs and ISGs). In conclusion, we have identified and experimentally validated repurposable anti-SARS-CoV-2 and IAV drugs using a systems biology approach, which may have the potential for treating these viral infections and their complications (sepsis).
2019年冠状病毒病（COVID-19）已经影响了全球人类生活的几乎方方面面，对人类健康构成了巨大威胁。新药研发时间紧迫，且迫切需要迅速控制疾病以降低死亡率，这促使人们寻找新型治疗方法的快速有效替代方案，例如药物重新利用。为了确定具有潜在重新利用价值的药物，我们采用了一种系统方法，通过将基于综合网络的细胞特征库项目中化学物质的基因表达扰动数据与来自轻度和重度COVID-19患者的公开单细胞RNA测序数据集（GEO：GSE145926，公开数据，于2020年4月22日获取）相结合，从美国食品药品监督管理局（FDA）批准的药物和临床前小分子化合物中挖掘候选药物。我们鉴定出281种FDA批准的药物有可能有效对抗严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染，其中16种目前正在进行临床试验以评估其对COVID-19的疗效。我们通过实验测试并证明了酪氨酸磷酸化抑制剂AG-1478和布雷菲德菌素A这两种糖基化（一种翻译后修饰）化学抑制剂对单链核糖核酸（ssRNA）病毒甲型流感病毒复制以及宿主细胞细胞因子及其调节剂（干扰素和干扰素刺激基因）转录和翻译的抑制作用。总之，我们使用系统生物学方法鉴定并通过实验验证了可重新利用的抗SARS-CoV-2和甲型流感病毒药物，这些药物可能具有治疗这些病毒感染及其并发症（脓毒症）的潜力。
