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IN VITRO ANTIVIRAL ACTIVITY OF THE ANTI-HCV DRUGS DACLATASVIR AND SOFOSBUVIR AGAINST SARS-COV-2, THE AETIOLOGICAL AGENT OF COVID-19
SARS-CoV-2
Medicamentos anti-HCV
Atividade antiviral in vitro
Daclatasvir
Sofosbuvir
SARS-CoV-2
In vitro antiviral activity
Drugs
Daclatasvir
Sofosbuvir
Autor
Afiliación
Resumen en ingles
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 pro teins. 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 lM, 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. Concentrations required for partial daclatasvir in vitro activity are achieved in plasma at Cmax after administration
of the approved dose to humans.
Palabras clave en portugues
Agente etiológico de COVID-19SARS-CoV-2
Medicamentos anti-HCV
Atividade antiviral in vitro
Daclatasvir
Sofosbuvir
Palabras clave en ingles
COVID-19SARS-CoV-2
In vitro antiviral activity
Drugs
Daclatasvir
Sofosbuvir
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