Prediction of repurposed drugs for treating lung injury in COVID-19 [version 2; peer review: 2 approved]
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, t...
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| Format: | Article |
| Language: | English |
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F1000 Research Ltd
2020-08-01
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| Series: | F1000Research |
| Online Access: | https://f1000research.com/articles/9-609/v2 |
| _version_ | 1818351812622680064 |
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| author | Bing He Lana Garmire |
| author_facet | Bing He Lana Garmire |
| author_sort | Bing He |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T18:43:41Z |
| format | Article |
| id | doaj.art-3a6fd670bf9146f8955821bd2fecb0d9 |
| institution | Directory Open Access Journal |
| issn | 2046-1402 |
| language | English |
| last_indexed | 2024-12-13T18:43:41Z |
| publishDate | 2020-08-01 |
| publisher | F1000 Research Ltd |
| record_format | Article |
| series | F1000Research |
| spelling | doaj.art-3a6fd670bf9146f8955821bd2fecb0d92022-12-21T23:35:08ZengF1000 Research LtdF1000Research2046-14022020-08-01910.12688/f1000research.23996.228930Prediction of repurposed drugs for treating lung injury in COVID-19 [version 2; peer review: 2 approved]Bing He0Lana Garmire1Department of Computational Medicine and Bioinformatics, Medical School, University of Michigan, Ann Arbor, 48105, USADepartment of Computational Medicine and Bioinformatics, Medical School, University of Michigan, Ann Arbor, 48105, USABackground: 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.https://f1000research.com/articles/9-609/v2 |
| spellingShingle | Bing He Lana Garmire Prediction of repurposed drugs for treating lung injury in COVID-19 [version 2; peer review: 2 approved] F1000Research |
| title | Prediction of repurposed drugs for treating lung injury in COVID-19 [version 2; peer review: 2 approved] |
| title_full | Prediction of repurposed drugs for treating lung injury in COVID-19 [version 2; peer review: 2 approved] |
| title_fullStr | Prediction of repurposed drugs for treating lung injury in COVID-19 [version 2; peer review: 2 approved] |
| title_full_unstemmed | Prediction of repurposed drugs for treating lung injury in COVID-19 [version 2; peer review: 2 approved] |
| title_short | Prediction of repurposed drugs for treating lung injury in COVID-19 [version 2; peer review: 2 approved] |
| title_sort | prediction of repurposed drugs for treating lung injury in covid 19 version 2 peer review 2 approved |
| url | https://f1000research.com/articles/9-609/v2 |
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