He Bing, Garmire Lana
Department of Computational Medicine and Bioinformatics, Medical School, University of Michigan, Ann Arbor, 48105, USA.
ArXiv. 2020 Mar 30:arXiv:2003.14333v2.
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.
冠状病毒病（COVID-19）是2019年发现的一种传染病，目前正在全球范围内爆发。伴有严重呼吸衰竭的肺损伤是COVID-19的主要死因，由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起。然而，对于COVID-19所致的肺损伤和急性呼吸衰竭，仍然缺乏有效的治疗方法。SARS-CoV-2刺突蛋白导致的血管紧张素转换酶2（ACE2）抑制是COVID-19肺损伤最合理的机制。基于COL-3（一种化学修饰的四环素）和CGP-60474（一种细胞周期蛋白依赖性激酶抑制剂）能够逆转用ACE2抑制剂处理的HCC515细胞以及人类COVID-19患者肺组织中的基因表达模式，我们提出将这两种候选药物用于治疗COVID-19中的肺损伤。进一步的生物信息学分析表明，用ACE2抑制剂处理的HCC515细胞与人类COVID-19患者肺组织之间有12条显著富集的通路（P值<0.05）重叠，包括已知与肺损伤相关的信号通路，如TNF信号通路、MAPK信号通路和趋化因子信号通路。所有这12条通路在COL-3处理的HCC515细胞中均有靶向作用，其中RHOA、RAC2、FAS、CDC42等基因的表达降低。CGP-60474与COL-3共享12条通路中的11条，具有共同的靶基因如RHOA。它还独特地靶向与肺损伤相关的基因，如CALR和MMP14。总之，本研究表明ACE2抑制可能是导致COVID-19肺损伤机制的一部分，并且COL-3和CGP-60474等化合物有作为其治疗的重新利用药物的潜力。
