论文标题
预测重新利用药物治疗Covid-19的肺损伤
Prediction of repurposed drugs for treating lung injury in COVID-19
论文作者
论文摘要
冠状病毒病（Covid-19）是一种在2019年发现的感染病，目前正在全球爆发。严重呼吸衰竭的肺损伤是Covid-19的主要原因，这是由严重的急性呼吸道综合征冠状病毒2（SARS-COV-2）带来的。然而，对于199诱导的肺损伤和急性呼吸衰竭，仍然缺乏有效的治疗。 SARS-COV-2的尖峰蛋白引起的血管紧张素转换酶2（ACE2）是Covid-19中最合理的机制。我们提出了两种候选药物Col-3（化学修饰的四环素）和CGP-60474（一种依赖细胞周期蛋白依赖性激酶抑制剂），用于治疗CoVID-19中的肺损伤，基于它们的能力，它们可以逆转HCC515细胞中ACE 2抑制剂和人类coviditor的HCC515细胞中的基因表达模式。进一步的生物信息学分析表明，用ACE2抑制剂和人类covid-19患者肺组织处理的HCC515细胞之间的十二个显着富集的途径（P值<0.05）重叠，包括已知与肺部损伤相关的信号途径，例如TNF信号，MAPK信号传递和趋化的信号信号和趋化的信号。所有这十二个途径均针对Col-3处理过的HCC515细胞，其中RHOA，RAC2，FAS，CDC42等基因降低了表达。 CGP-60474与col-3共享十二个途径的11个途径，与RhoA等共同的靶基因。它还唯一地靶向与肺损伤有关的基因，例如CALR和MMP14。总而言之，这项研究表明，ACE2抑制可能是导致COVID-19的肺损伤的机制的一部分，而Col-3和CGP-60474等化合物具有重新塑造药物的治疗药物。
Coronavirus disease (COVID-19) is an infectious disease discovered in 2019 and currently in outbreak across the world. Lung injury with severe respiratory failure is the leading cause of death in COVID-19, brought by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there still lacks efficient treatment for COVID-19 induced lung injury and acute respiratory failure. Inhibition of Angiotensin-converting enzyme 2 (ACE2) caused by spike protein of SARS-CoV-2 is the most plausible mechanism of lung injury in COVID-19. We propose two candidate drugs, COL-3 (a chemically modified tetracycline) and CGP-60474 (a cyclin-dependent kinase inhibitor), for treating lung injuries in COVID-19, based on their abilities to reverse the gene expression patterns in HCC515 cells treated with ACE2 inhibitor and in human COVID-19 patient lung tissues. Further bioinformatics analysis shows that twelve significantly enriched pathways (P-value <0.05) overlap between HCC515 cells treated with ACE2 inhibitor and human COVID-19 patient lung tissues, including signaling pathways known to be associated with lung injury such as TNF signaling, MAPK signaling and Chemokine signaling pathways. All these twelve pathways are targeted in COL-3 treated HCC515 cells, in which genes such as RHOA, RAC2, FAS, CDC42 have reduced expression. CGP-60474 shares eleven of twelve pathways with COL-3 with common target genes such as RHOA. It also uniquely targets genes related to lung injury, such as CALR and MMP14. In summary, this study shows that ACE2 inhibition is likely part of the mechanisms leading to lung injury in COVID-19, and that compounds such as COL-3 and CGP-60474 have the potential as repurposed drugs for its treatment.
