  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.
