In vitro antiviral activity of the anti-HCV drugs daclatasvir and sofosbuvir against SARS-CoV-2, the aetiological agent of COVID-19.

Autor:	Sacramento CQ; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil., Fintelman-Rodrigues N; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil., Temerozo JR; Laboratório de Pesquisas sobre o Timo, IOC, Fiocruz, Rio de Janeiro, RJ, Brazil.; National Institute for Science and Technology on Neuroimmunomodulation (INCT/NIM), IOC, Fiocruz, Rio de Janeiro, RJ, Brazil., Da Silva APD; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil., Dias SDSG; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil., da Silva CDS; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil., Ferreira AC; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil.; Universidade Iguaçu, Nova Iguaçu, RJ, Brazil., Mattos M; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil., Pão CRR; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil., de Freitas CS; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil., Soares VC; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil., Hoelz LVB; Instituto de Tecnologia de Fármacos (Farmanguinhos), Fiocruz, Rio de Janeiro, RJ, Brazil., Fernandes TVA; Instituto de Tecnologia de Fármacos (Farmanguinhos), Fiocruz, Rio de Janeiro, RJ, Brazil.; Laboratório de Macromoléculas, Diretoria de Metrologia Aplicada às Ciências da Vida, Instituto Nacional de Metrologia, Qualidade e Tecnologia-INMETRO, Duque de Caxias, RJ 25250-020, Brazil., Branco FSC; Instituto de Tecnologia de Fármacos (Farmanguinhos), Fiocruz, Rio de Janeiro, RJ, Brazil., Bastos MM; Instituto de Tecnologia de Fármacos (Farmanguinhos), Fiocruz, Rio de Janeiro, RJ, Brazil., Boechat N; Instituto de Tecnologia de Fármacos (Farmanguinhos), Fiocruz, Rio de Janeiro, RJ, Brazil., Saraiva FB; Instituto de Tecnologia em Imunobiológicos (Bio-Manguinhos), Fiocruz, Rio de Janeiro, RJ, Brazil., Ferreira MA; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil.; Instituto de Tecnologia em Imunobiológicos (Bio-Manguinhos), Fiocruz, Rio de Janeiro, RJ, Brazil., Jockusch S; Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027, USA.; Department of Chemistry, Columbia University, New York, NY 10027, USA., Wang X; Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027, USA.; Department of Chemical Engineering, Columbia University, New York, NY 10027, USA., Tao C; Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027, USA.; Department of Chemical Engineering, Columbia University, New York, NY 10027, USA., Chien M; Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027, USA.; Department of Chemical Engineering, Columbia University, New York, NY 10027, USA., Xie W; Laboratory of Structural Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA., Patel D; Laboratory of Structural Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA., Garzia A; Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY 10065, USA., Tuschl T; Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY 10065, USA., Russo JJ; Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027, USA.; Department of Chemical Engineering, Columbia University, New York, NY 10027, USA., Rajoli RKR; Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L7 3NY, UK., Pedrosa CSG; Instituto D'Or de Pesquisa e Ensino, Rio de Janeiro, RJ, Brazil., Vitória G; Instituto D'Or de Pesquisa e Ensino, Rio de Janeiro, RJ, Brazil., Souza LRQ; Instituto D'Or de Pesquisa e Ensino, Rio de Janeiro, RJ, Brazil., Goto-Silva L; Instituto D'Or de Pesquisa e Ensino, Rio de Janeiro, RJ, Brazil., Guimarães MZ; Instituto D'Or de Pesquisa e Ensino, Rio de Janeiro, RJ, Brazil.; Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil., Rehen SK; Instituto D'Or de Pesquisa e Ensino, Rio de Janeiro, RJ, Brazil.; Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil., Owen A; Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L7 3NY, UK., Bozza FA; Instituto D'Or de Pesquisa e Ensino, Rio de Janeiro, RJ, Brazil.; Instituto Nacional de Infectologia Evandro Chagas, Fiocruz, Rio de Janeiro, RJ, Brazil., Bou-Habib DC; Laboratório de Pesquisas sobre o Timo, IOC, Fiocruz, Rio de Janeiro, RJ, Brazil.; National Institute for Science and Technology on Neuroimmunomodulation (INCT/NIM), IOC, Fiocruz, Rio de Janeiro, RJ, Brazil., Ju J; Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027, USA.; Department of Chemical Engineering, Columbia University, New York, NY 10027, USA.; Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY, 10032, USA., Bozza PT; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil., Souza TML; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil.
Jazyk:	angličtina
Zdroj:	The Journal of antimicrobial chemotherapy [J Antimicrob Chemother] 2021 Jun 18; Vol. 76 (7), pp. 1874-1885.
DOI:	10.1093/jac/dkab072
Abstrakt:	Background: 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. Methods: 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. Results: 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. Conclusions: Daclatasvir, alone or in combination with sofosbuvir, at higher doses than used against HCV, may be further fostered as an anti-COVID-19 therapy. (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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