Advances in the computational landscape for repurposed drugs against COVID-19.
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ABSTRACT:
SUBMITTER: Aronskyy I
PROVIDER: S-EPMC8323501 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The COVID-19 pandemic caused by SARS-CoV-2 has placed severe constraints on healthcare systems around the globe. The SARS-CoV-2 virus has caused upheaval in the healthcare and economic sectors worldwide. On the 20th of May 2020, the World Health Organisation declared COVID-19 a global pandemic due to the unprecedented number of cases reported around the globe. As of the 4th of November 2022, there were 637,117,429 coronavirus cases reported globally by Worldometer stats, with 6,602,572 related deaths. In South Africa, there were approximately 4,029,496 coronavirus cases and 102,311 associated deaths. As such, there is a need for efficacious therapeutic regimes. There has been a paucity of knowledge encompassing the use of effective and specific antiviral drug therapies for treating COVID-19 since the outbreak. In this review, we provide valuable insights into the repurposing of current drugs for COVID-19. Drug repurposing provides a suitable option for the discovery of efficacious drugs for COVID-19, thereby decreasing the costs and turnaround times of drug development strategies. This review provides an overview of ten drugs, including antimalarial, antiparasitic, anti-inflammatory, nucleoside analogue, monoclonal-antibody drugs, that were repurposed for the potential treatment of COVID-19.
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Project description:The SARS-CoV-2 virus needs multiple copies for its multiplication using an enzyme RNA-dependent RNA polymerase (RdRp). Remdesivir inhibits viral RdRp, controls the multiplication of the virus, and protects patients. However, treatment of COVID-19 with remdesivir involves adverse effects. Many ongoing clinical trials are exploring the potential of the combination of remdesivir with repurposed drugs by targeting multiple targets of virus and host human simultaneously. Better results were obtained with the remdesivir-baricitinib combination treatment for COVID-19 compared to the treatment with remdesivir alone. Notably, recovery from COVID-19 was found to be 8 days less via the remdesivir-baricitinib combination treatment as compared to remdesivir treatment alone. Furthermore, the mortality rate via the remdesivir-baricitinib combination treatment was lower compared to the remdesivir-only treatment. Remdesivir targets the SARS-CoV-2 enzyme while baricitinib targets the host human enzyme. Simultaneously, remdesivir and baricitinib as a combination inhibit their target viral RdRp and human Janus kinase, respectively. Ongoing trials for the combination of drugs will suggest in the future whether they may reduce the recovery time, reduce the mortality rate, and improve patient clinical status for noninvasive ventilation. In the future, simultaneously targeting virus replication enzymes and host human kinases may be the strategy for SARS-CoV-2 therapeutics.
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Project description: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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Project 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.
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