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Underlying Mechanisms and Candidate Drugs for COVID-19 Based on the Connectivity Map Database
Frontiers in Genetics ( IF 2.8 ) Pub Date : 2020-09-04 , DOI: 10.3389/fgene.2020.558557
Zhonglin Li 1 , Ling Yang 1
Affiliation  

Background

The coronavirus disease 2019 (COVID-19) has become a worldwide public health crisis. At present, there are no effective antiviral drugs to treat COVID-19. Although some vaccines have been developed, late-stage clinical trials that allow licensure by regulatory agencies are still needed. Previous reports have indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV are highly homologous and both use angiotensin-converting enzyme 2 (ACE2) as the receptor to enter cells, and SARS-CoV infection reduces the ACE2 expression in the lung. Therefore, the analysis of genes co-expressed with ACE2 in the lung may uncover the underlying mechanism of COVID-19. Finally, we used the Connectivity map (Cmap) database to search for candidate drugs using transcriptome profiles of patients with COVID-19.

Method

Based on the differentially expressed genes (DEGs), indicated by the expression of RNAs isolated from bronchoalveolar lavage fluid (BALF) cells of patients with COVID-19, we performed functional enrichment analysis and hub gene cluster analysis. Furthermore, we identified genes co-expressed with ACE2 in healthy lung samples and analyzed the significant genes. Additionally, to identify several candidate drugs for the treatment of COVID-19, we queried Cmap using DEGs and genes co-expressed with ACE2.

Results and Conclusion

The up-regulated genes in the BALF cells of patients with COVID-19 are related to viral mRNA translation. The down-regulated genes are related to immune response functions. Genes positively correlated with ACE2 are related to immune defense and those negatively correlated are enriched in synaptic transmission functions. The results reflected prosperous viral proliferation and immune dysfunction in patients. Furthermore, ACE2 may not only mediate viral entrance, but also play an important role in immune defense. By using Cmap with transcriptome profiles of patients with COVID-19, we identified candidate drugs for the treatment of COVID-19, such as amantadine and acyclovir.



中文翻译:

基于连通图数据库的 COVID-19 潜在机制和候选药物

Background

2019 年冠状病毒病 (COVID-19) 已成为全球公共卫生危机。目前,没有有效的抗病毒药物来治疗 COVID-19。尽管已经开发了一些疫苗,但仍需要允许监管机构许可的后期临床试验。此前的报道表明,严重急性呼吸综合征冠状病毒2(SARS-CoV-2)与SARS-CoV高度同源,均以血管紧张素转化酶2(ACE2)为受体进入细胞,SARS-CoV感染可降低ACE2在肺中的表达。因此,对肺中与 ACE2 共表达的基因的分析可能会揭示 COVID-19 的潜在机制。最后,我们使用连接图 (Cmap) 数据库使用 COVID-19 患者的转录组谱搜索候选药物。

Method

基于从 COVID-19 患者的支气管肺泡灌洗液 (BALF) 细胞中分离的 RNA 的表达所表明的差异表达基因 (DEG),我们进行了功能富集分析和中枢基因聚类分析。此外,我们在健康肺样本中鉴定了与 ACE2 共表达的基因,并分析了重要基因。此外,为了确定治疗 COVID-19 的几种候选药物,我们使用 DEG 和与 ACE2 共表达的基因查询 Cmap。

Results and Conclusion

COVID-19 患者 BALF 细胞中上调的基因与病毒 mRNA 翻译有关。下调的基因与免疫反应功能有关。与ACE2正相关的基因与免疫防御有关,而与ACE2负相关的基因则富含突触传递功能。结果反映了患者的病毒增殖旺盛和免疫功能障碍。此外,ACE2不仅可以介导病毒进入,而且在免疫防御中也发挥着重要作用。通过使用 Cmap 和 COVID-19 患者的转录组谱,我们确定了治疗 COVID-19 的候选药物,例如金刚烷胺和阿昔洛韦。

更新日期:2020-10-28
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