Prediction of repurposed drugs for treating lung injury in COVID-19

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.

Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells

“…Panobinostat had the strongest effect on limiting SARS-CoV-2 replication whilst maintaining cell viability, and completely blocked replication of SARS-CoV-2 at all doses tested ( Fig 5 ); however, if cells were infected prior to treatment a more modest effect on replication were observed. This difference may be related to the recent observations that panobinostat can suppress ACE2 expression [ 32 ], which would explain its beneficial effect prior to entry of the virus into cells and not thereafter. Abemaciclib (LY2835219) is another cell cycle inhibitor, suppressor of DNA replication and anti-cancer drug that emerged from the screen however these are likely to be detrimental to recovery from SARS-CoV-2 infection.…”

Differential Co-Expression Network Analysis Reveals Key Hub-High Traffic Genes as Potential Therapeutic Targets for COVID-19 Pandemic

“…Blocking the NFkB1 inhibitory protein (IkB) induces the NFkB1 transcription factor, which increases transcription of cytokine genes ( 86 – 88 ). This pathway has been considered an attractive therapeutic target for COVID-19-induced lung injury ( 86 , 89 ).…”

Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells

“…Panobinostat had the strongest effect on limiting SARS-CoV-2 replication whilst maintaining cell viability, and completely blocked replication of SARS-CoV-2 at all doses tested (Figure 5); however, if cells were infected prior to treatment a more modest effect on replication were observed. This difference may be related to the recent observations that panobinostat can suppress ACE2 expression (He and Garmire, 2020), which would explain its beneficial effect prior to entry of the virus into cells and not thereafter. Abemaciclib (LY2835219) is another cell cycle inhibitor, suppressor of DNA replication and anti-cancer drug that emerged from the screen however these are likely to be detrimental to recovery from SARS-CoV-2 infection.…”