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Published on: February 12, 2019
Prediction of repurposed drugs for treating lung injury in COVID-19
1Department of Computational Medicine and Bioinformatics, Medical School, University of Michigan, Ann Arbor, 48105, USA.
Insights
Two potential drugs, COL-3 and CGP-60474, show promise for treating COVID-19 lung injury by targeting pathways affected by SARS-CoV-2 spike protein's ACE2 inhibition.
Area of Science:
- Biomedical Research
- Molecular Biology
- Pharmacology
Background:
- Coronavirus disease (COVID-19), caused by SARS-CoV-2, leads to severe lung injury and acute respiratory failure, with limited effective treatments.
- Inhibition of Angiotensin-converting enzyme 2 (ACE2) by the SARS-CoV-2 spike protein is a key mechanism implicated in COVID-19 lung injury.
- Existing treatments for COVID-19-induced lung injury are insufficient, necessitating the exploration of novel therapeutic strategies.
Approach:
- Investigated the mechanism of COVID-19 lung injury by analyzing gene expression patterns in HCC515 cells treated with an ACE2 inhibitor and in human COVID-19 patient lung tissues.
- Utilized bioinformatics to identify overlapping significantly enriched pathways associated with lung injury in both experimental models.
- Evaluated the potential of two candidate drugs, COL-3 (a chemically modified tetracycline) and CGP-60474 (a cyclin-dependent kinase inhibitor), to reverse these disease-associated gene expression patterns.
Key Points:
- Twelve significantly enriched pathways, including TNF, MAPK, and Chemokine signaling, were common to both ACE2-inhibited cells and COVID-19 lung tissues.
- COL-3 demonstrated the ability to target all twelve identified pathways, reducing the expression of key genes like RHOA, RAC2, FAS, and CDC42.
- CGP-60474 targeted eleven of the twelve pathways, sharing RHOA as a common target with COL-3, and also uniquely affected CALR and MMP14, genes linked to lung injury.
Conclusions:
- ACE2 inhibition by SARS-CoV-2 is a critical factor contributing to lung injury in COVID-19.
- COL-3 and CGP-60474 show potential as repurposed drugs for treating COVID-19-related lung injury due to their ability to modulate key molecular pathways.
- Further research into these compounds could lead to novel therapeutic interventions for patients suffering from severe COVID-19 respiratory complications.
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.
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