Sacramento, Carolina Q, Fintelman-Rodrigues, Natalia, Temerozo, Jairo R, Dias Da Silva, Aline de Paula, Gomes Dias, Suelen da Silva, da Silva, Carine dos Santos, Ferreira, Andre C, Mattos, Mayara, Pao, Camila RR, de Freitas, Caroline S et al (show 30 more authors)
(2021)
<i>In vitro</i> antiviral activity of the anti-HCV drugs daclatasvir and sofosbuvir against SARS-CoV-2, the aetiological agent of COVID-19.
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 76 (7).
pp. 1874-1885.
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In vitro antiviral activity of the anti-HCV drugs daclatasvir and sofosbuvir against SARS-CoV-2, the aetiological agent of C.pdf - Author Accepted Manuscript Download (1MB) | Preview |
Abstract
<h4>Background</h4>Current approaches of drug repurposing against COVID-19 have not proven overwhelmingly successful and the SARS-CoV-2 pandemic continues to cause major global mortality. SARS-CoV-2 nsp12, its RNA polymerase, shares homology in the nucleotide uptake channel with the HCV orthologue enzyme NS5B. Besides, HCV enzyme NS5A has pleiotropic activities, such as RNA binding, that are shared with various SARS-CoV-2 proteins. Thus, anti-HCV NS5B and NS5A inhibitors, like sofosbuvir and daclatasvir, respectively, could be endowed with anti-SARS-CoV-2 activity.<h4>Methods</h4>SARS-CoV-2-infected Vero cells, HuH-7 cells, Calu-3 cells, neural stem cells and monocytes were used to investigate the effects of daclatasvir and sofosbuvir. In silico and cell-free based assays were performed with SARS-CoV-2 RNA and nsp12 to better comprehend the mechanism of inhibition of the investigated compounds. A physiologically based pharmacokinetic model was generated to estimate daclatasvir's dose and schedule to maximize the probability of success for COVID-19.<h4>Results</h4>Daclatasvir inhibited SARS-CoV-2 replication in Vero, HuH-7 and Calu-3 cells, with potencies of 0.8, 0.6 and 1.1 μM, respectively. Although less potent than daclatasvir, sofosbuvir alone and combined with daclatasvir inhibited replication in Calu-3 cells. Sofosbuvir and daclatasvir prevented virus-induced neuronal apoptosis and release of cytokine storm-related inflammatory mediators, respectively. Sofosbuvir inhibited RNA synthesis by chain termination and daclatasvir targeted the folding of secondary RNA structures in the SARS-CoV-2 genome. Concentrations required for partial daclatasvir in vitro activity are achieved in plasma at Cmax after administration of the approved dose to humans.<h4>Conclusions</h4>Daclatasvir, alone or in combination with sofosbuvir, at higher doses than used against HCV, may be further fostered as an anti-COVID-19 therapy.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Vero Cells, Animals, Humans, Carbamates, Imidazoles, Pyrrolidines, Valine, RNA, Viral, Pharmaceutical Preparations, Antiviral Agents, Sofosbuvir, Chlorocebus aethiops, COVID-19, SARS-CoV-2 |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 30 Nov 2023 16:56 |
| Last Modified: | 30 Nov 2023 16:56 |
| DOI: | 10.1093/jac/dkab072 |
| Open Access URL: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC80832... |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3177114 |
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