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.