[论文解读] Prediction of repurposed drugs for treating lung injury in COVID-19

Bing He, Lana X. Garmire|arXiv (Cornell University)|Mar 30, 2020

COVID-19 Clinical Research Studies参考文献 54被引用 4

一句话总结

本研究鉴定出COL-3（一种修饰四环素）和CGP-60474（一种周期素依赖性激酶抑制剂）为治疗COVID-19相关肺损伤的潜在老药新用药物候选。通过逆转ACE2抑制诱导的HCC515肺细胞及人患者肺组织中的基因表达变化，这两种化合物调节了12条与肺损伤相关的重叠通路，包括TNF、MAPK和趋化因子信号通路，关键基因如RHOA、RAC2和FAS表达下调。

ABSTRACT

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.

研究动机与目标

• 鉴定可逆转COVID-19患者肺损伤机制的老药新用药物。
• 研究SARS-CoV-2刺突蛋白介导的ACE2抑制在驱动肺损伤通路中的作用。
• 比较ACE2抑制的HCC515肺细胞与人类COVID-19患者肺组织的基因表达谱。
• 评估能逆转两种模型中共有的失调通路的药物候选。
• 优先选择在通路调节范围和与肺损伤相关的关键基因重叠方面表现优异的化合物。

提出的方法

• 使用ACE2抑制剂处理HCC515人肺上皮细胞以模拟SARS-CoV-2诱导的肺损伤。
• 进行转录组谱分析，鉴定ACE2抑制HCC515细胞中差异表达的基因。
• 将ACE2抑制HCC515细胞的基因表达特征与人类COVID-19患者肺组织的表达谱进行比较。
• 识别出12条在ACE2抑制HCC515细胞和患者肺组织中显著富集的通路（P < 0.05）。
• 筛选药物候选（COL-3和CGP-60474）在HCC515细胞中逆转失调基因表达模式的能力。
• 进行生物信息学分析，评估药物与疾病模型之间通路重叠及靶基因汇聚情况。

实验结果

研究问题

• RQ1 哪些药物候选能逆转肺上皮细胞中ACE2抑制诱导的基因表达变化？
• RQ2 ACE2抑制HCC515细胞的转录组谱与COVID-19患者肺组织的转录组谱在多大程度上重叠？
• RQ3 哪些信号通路在ACE2抑制HCC515细胞和人类COVID-19肺组织中均出现失调？
• RQ4 COL-3和CGP-60474如何调节与COVID-19肺损伤相关的关键通路和靶基因？
• RQ5 老药新用药物在对抗SARS-CoV-2诱导肺损伤的分子机制方面具有何种潜力？

主要发现

• ACE2抑制HCC515细胞与人类COVID-19患者肺组织之间存在12条显著富集的重叠通路（P < 0.05），包括TNF、MAPK和趋化因子信号通路。
• COL-3治疗逆转了所有12条重叠通路的失调，关键基因如RHOA、RAC2、FAS和CDC42的表达水平降低。
• CGP-60474与COL-3共享11条重叠通路，并且还特异性靶向与肺损伤相关的基因如CALR和MMP14。
• 两种药物均调节了炎症和纤维化的核心调控因子，提示其在减轻COVID-19相关肺损伤方面具有潜力。
• 本研究基于药物逆转疾病相关基因表达特征的能力，为老药新用COL-3和CGP-60474提供了系统生物学依据。
• ACE2抑制被确定为COVID-19肺损伤的潜在机制，其分子机制在细胞模型与患者组织模型之间表现出转录组汇聚特征。