Abstract
Background: 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, caused 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. Methods: Inhibition of angiotensin-converting enzyme 2 (ACE2) caused by the spike protein of SARS-CoV-2 is the most plausible mechanism of lung injury in COVID-19. We performed drug repositioning analysis to identify drug candidates that reverse gene expression pattern in L1000 lung cell line HCC515 treated with ACE2 inhibitor. We confirmed these drug candidates by similar bioinformatics analysis using lung tissues from patients deceased from COVID-19. We further investigated deregulated genes and pathways related to lung injury, as well as the gene-pathway-drug candidate relationships. Results: 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. Further bioinformatics analysis shows that 12 significantly enriched pathways (P-value <0.05) overlap between HCC515 cells treated with ACE2 inhibitor and human COVID-19 patient lung tissues. These include signaling pathways known to be associated with lung injury such as TNF signaling, MAPK signaling and chemokine signaling pathways. All 12 pathways are targeted in COL-3 treated HCC515 cells, in which genes such as RHOA, RAC2, FAS, CDC42 have reduced expression. CGP-60474 shares 11 of 12 pathways with COL-3 and common target genes such as RHOA. It also uniquely targets other genes related to lung injury, such as CALR and MMP14. Conclusions: 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 potential as repurposed drugs for its treatment.
Highlights
Coronavirus disease 2019 (COVID-19) is an infectious disease discovered in 2019 and currently in outbreak across the world, resulting in more than 4.3 million infections and over 291,354 deaths as of 12th May, 2020
As COVID-19 is an emerging disease with much unknown, we first demonstrate the feasibility of the drug repositioning pipeline using H1N1 virus infection, where much more research has been done and multiple drugs are approved by the United States Food and Drug Administration
The results show that CGP-60474 (FDR= 2.514×10-4), sirolimus (FDR= 3.040×10-4), COL-3 (FDR= 9.452×10-4), PIK-75 (FDR= 0.002), geldanamycin (FDR= 0.001), and wortmannin (FDR= 0.046) could significantly (FDR
Summary
Coronavirus disease 2019 (COVID-19) is an infectious disease discovered in 2019 and currently in outbreak across the world, resulting in more than 4.3 million infections and over 291,354 deaths as of 12th May, 2020. Since in SARS-CoV infection, the spike protein of SARS-CoV inhibits ACE2 to cause severe lung injury and acute respiratory failure[10,11], it is highly likely that SARS-CoV-2 uses the same mechanism. We performed drug repositioning analysis to identify drug candidates that reverse gene expression pattern in L1000 lung cell line HCC515 treated with ACE2 inhibitor. We confirmed these drug candidates by similar bioinformatics analysis using lung tissues from patients deceased from COVID-19. Further bioinformatics analysis shows that 12 significantly enriched pathways (P-value
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