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

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.

Figure 1.. Workflow of repurposing drugs for treating lung injury in COVID-19.

Input data include gene expression in A549 cells with H1N1 infection, HCC515 cells with ACE2 inhibitor (ACE2i), human lung tissues from COVID-19 deceased patients and cells with drug treatment, respectively. Reversing analysis is conducted to search for drugs which can reverse the gene expression changes upon the treatment. The candidate drug to is compared to all other drugs and compounds, in order to estimate its significance level at treating the disease. Candidate drugs for H1N1 are used for validation of the computational pipeline. Candidate drugs identified in both HCC515 cells treated with ACE2 inhibitor and in human lung tissues from COVID-19 deceased patients are used for downstream mechanism analysis.

Figure 2.. COL-3 and CGP-60474 can reverse the expression of marker genes of lung injury.

Z-score: z score of differential expression of genes in the sample; ACE2i: HCC515 cells with ACE2 inhibitor inhibition; SARS-CoV-2: human lung tissues from COVID-19 patients deceased from SARS-CoV-2 induced lung complications; COL-3: HCC515 cells treated with COL-3; CGP-60474: HCC515 cells treated with CGP-60474.

Figure 3.. The bubble plot of significantly enriched pathways in HCC515 cells with ACE2 inhibitor inhibition and human COVID-19 patient lung tissues.

X-axis and Y-axis show -log10 transformed P-values in human COVID-19 patient lung tissues (SARS-CoV-2) and HCC515 cells with ACE2 inhibitor inhibition (ACE2i), respectively. Size of the bubble shows the average value of -log10 transformed P-value in SARS-CoV-2 and ACE2i.

Figure 4.

Target genes and pathways of COL-3 and CGP-60474 in treating lung injury in COVID-19. All pathways were significant enriched in both human COVID-19 patient lung tissues and HCC515 cells with ACE2 inhibitor inhibition. The abnormal gene expression patterns in these pathways were reversed by COL-3 and/or CGP-60474. Blue diamond: Down-regulated gene in disease; Orange diamond: Up-regulated gene in disease; Hexagon: Pathway; Blue line: Drug decreases gene expression; Orange line: drug increases gene expression; Blue/Orange line width corresponds to the ability to change gene expression; Dark green line: Interaction between gene and pathway; Diamond size: Importance of gene in the disease; Hexagon size: Importance of pathway in the disease.

Figure 5.

Proposed mechanisms of lung injury in COVID-19 through ACE2 and the therapeutic effects of COL-3 and CGP-60474.