Table2_Glycyrrhizic Acid for COVID-19: Findings of Targeting Pivotal Inflammatory Pathways Triggered by SARS-CoV-2.xls

Background: Coronavirus disease 2019 (COVID-19) is now a worldwide public health crisis. The causative pathogen is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Novel therapeutic agents are desperately needed. Because of the frequent mutations in the virus and its ability to cause cytokine storms, targeting the viral proteins has some drawbacks. Targeting cellular factors or pivotal inflammatory pathways triggered by SARS-CoV-2 may produce a broader range of therapies. Glycyrrhizic acid (GA) might be beneficial against SARS-CoV-2 because of its anti-inflammatory and antiviral characteristics and possible ability to regulate crucial host factors. However, the mechanism underlying how GA regulates host factors remains to be determined.
Methods: In our report, we conducted a bioinformatics analysis to identify possible GA targets, biological functions, protein-protein interactions, transcription-factor-gene interactions, transcription-factor-miRNA coregulatory networks, and the signaling pathways of GA against COVID-19.
Results: Protein-protein interactions and network analysis showed that ICAM1, MMP9, TLR2, and SOCS3 had higher degree values, which may be key targets of GA for COVID-19. GO analysis indicated that the response to reactive oxygen species was significantly enriched. Pathway enrichment analysis showed that the IL-17, IL-6, TNF-α, IFN signals, complement system, and growth factor receptor signaling are the main pathways. The interactions of TF genes and miRNA with common targets and the activity of TFs were also recognized.
Conclusions: GA may inhibit COVID-19 through its anti-oxidant, anti-viral, and anti-inflammatory effects, and its ability to activate the immune system, and targeted therapy for those pathways is a predominant strategy to inhibit the cytokine storms triggered by SARS-CoV-2 infection.

背景：2019冠状病毒病（Coronavirus disease 2019, COVID-19）目前已演变为全球性公共卫生危机，其致病病原体为严重急性呼吸综合征冠状病毒2（severe acute respiratory syndrome coronavirus 2, SARS-CoV-2）。当前亟需研发新型治疗药物。由于该病毒频繁发生突变且可引发细胞因子风暴（cytokine storms），靶向病毒蛋白的治疗策略存在一定局限性。而靶向宿主细胞因子或SARS-CoV-2触发的关键炎症通路，有望开发出覆盖范围更广的治疗方案。甘草酸（Glycyrrhizic acid, GA）因其抗炎、抗病毒特性以及调控关键宿主因子的潜在能力，或可用于对抗SARS-CoV-2感染，但甘草酸调控宿主因子的具体分子机制仍有待阐明。
方法：本研究通过生物信息学分析，筛选甘草酸抗2019冠状病毒病的潜在作用靶点、生物学功能、蛋白质相互作用（protein-protein interactions）、转录因子-基因相互作用（transcription-factor-gene interactions）、转录因子-微小核糖核酸（microRNA, miRNA）共调控网络以及相关信号通路。
结果：蛋白质相互作用与网络分析显示，细胞间黏附分子1（Intercellular Adhesion Molecule 1, ICAM1）、基质金属蛋白酶9（Matrix Metalloproteinase 9, MMP9）、Toll样受体2（Toll-like Receptor 2, TLR2）以及细胞因子信号转导抑制因子3（Suppressor Of Cytokine Signaling 3, SOCS3）的节点度值更高，可能为甘草酸抗2019冠状病毒病的关键靶点。基因本体（Gene Ontology, GO）富集分析表明，活性氧应答通路显著富集。通路富集分析显示，白细胞介素17（Interleukin-17, IL-17）、白细胞介素6（Interleukin-6, IL-6）、肿瘤坏死因子α（Tumor Necrosis Factor-α, TNF-α）、干扰素（Interferon, IFN）信号通路、补体系统以及生长因子受体信号通路为主要富集通路。本研究同时明确了转录因子（Transcription Factor, TF）基因与miRNA的共同靶点相互作用以及转录因子的活性调控特征。
结论：甘草酸可通过抗氧化、抗病毒、抗炎作用以及激活免疫系统的能力抑制2019冠状病毒病，靶向上述通路的治疗策略是抑制SARS-CoV-2感染引发的细胞因子风暴的主要手段。