{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Sacramento CQ"],"funding":["Oswaldo Cruz Foundation","Conselho Nacional de Desenvolvimento Científico e Tecnológico","Jack Ma Foundation","Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro","Carlos Morel","Coordenaçaõ de Aperfeiçoamento de Pessoal de Nível Superior—Brasil","Inova Program","NCI NIH HHS","Engineering and Physical Sciences Research Council","National Institutes of Science and Technology Program"],"pagination":["1874-1885"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8083231"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["76(7)"],"pubmed_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."],"journal":["The Journal of antimicrobial chemotherapy"],"pubmed_title":["In vitro antiviral activity of the anti-HCV drugs daclatasvir and sofosbuvir against SARS-CoV-2, the aetiological agent of COVID-19."],"pmcid":["PMC8083231"],"funding_grant_id":["EP/R024804/1","P30 CA008748"],"pubmed_authors":["Patel D","Pao CRR","Fernandes TVA","Da Silva APD","Soares VC","Russo JJ","Hoelz LVB","Rajoli RKR","Souza TML","Tuschl T","de Freitas CS","da Silva CDS","Owen A","Wang X","Garzia A","Pedrosa CSG","Fintelman-Rodrigues N","Sacramento CQ","Dias SDSG","Xie W","Jockusch S","Bozza PT","Ferreira AC","Tao C","Chien M","Souza LRQ","Boechat N","Bou-Habib DC","Vitoria G","Guimaraes MZ","Goto-Silva L","Bozza FA","Temerozo JR","Ferreira MA","Rehen SK","Ju J","Mattos M","Bastos MM","Branco FSC","Saraiva FB"],"additional_accession":[]},"is_claimable":false,"name":"In vitro antiviral activity of the anti-HCV drugs daclatasvir and sofosbuvir against SARS-CoV-2, the aetiological agent of COVID-19.","description":"<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.","dates":{"release":"2021-01-01T00:00:00Z","publication":"2021 Jun","modification":"2026-05-08T07:04:24.89Z","creation":"2025-04-05T21:36:35.076Z"},"accession":"S-EPMC8083231","cross_references":{"pubmed":["33880524"],"doi":["10.1093/jac/dkab072"]}}