RT Journal Article
SR Electronic
T1 The <em>in vitro</em> antiviral activity of the anti-hepatitis C virus (HCV) drugs daclatasvir and sofosbuvir against SARS-CoV-2
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.15.153411
DO 10.1101/2020.06.15.153411
A1 Carolina Q. Sacramento
A1 Natalia Fintelman-Rodrigues
A1 Jairo R. Temerozo
A1 Aline de Paula Dias Da Silva
A1 Suelen da Silva Gomes Dias
A1 Carine dos Santos da Silva
A1 André C. Ferreira
A1 Mayara Mattos
A1 Camila R. R. Pão
A1 Caroline S. de Freitas
A1 Vinicius Cardoso Soares
A1 Lucas Villas Bôas Hoelz
A1 Tácio Vinício Amorim Fernandes
A1 Frederico Silva Castelo Branco
A1 Mônica Macedo Bastos
A1 Núbia Boechat
A1 Felipe B. Saraiva
A1 Marcelo Alves Ferreira
A1 Rajith K. R. Rajoli
A1 Carolina S. G. Pedrosa
A1 Gabriela Vitória
A1 Letícia R. Q. Souza
A1 Livia Goto-Silva
A1 Marilia Zaluar Guimarães
A1 Stevens K. Rehen
A1 Andrew Owen
A1 Fernando A. Bozza
A1 Dumith Chequer Bou-Habib
A1 Patrícia T. Bozza
A1 Thiago Moreno L. Souza
YR 2020
UL http://biorxiv.org/content/early/2020/10/16/2020.06.15.153411.abstract
AB Current approaches of drugs repurposing against 2019 coronavirus disease (COVID-19) have not proven overwhelmingly successful and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to cause major global mortality. Daclatasvir (DCV) and sofosbuvir (SFV) are clinically approved against hepatitis C virus (HCV), with satisfactory safety profile. DCV and SFV target the HCV enzymes NS5A and NS5B, respectively. NS5A is endowed with pleotropic activities, which overlap with several proteins from SARS-CoV-2. HCV NS5B and SARS-CoV-2 nsp12 are RNA polymerases that share homology in the nucleotide uptake channel. We thus tested whether SARS-COV-2 would be susceptible these anti-HCV drugs. DCV consistently inhibited the production of infectious SARS-CoV-2 in Vero cells, in the hepatoma cell line (HuH-7) and in type II pneumocytes (Calu-3), with potencies of 0.8, 0.6 and 1.1 μM, respectively. Although less potent than DCV, SFV and its nucleoside metabolite inhibited replication in Calu-3 cells. Moreover, SFV/DCV combination (1:0.15 ratio) inhibited SARS-CoV-2 with EC50 of 0.7:0.1 μM in Calu-3 cells. SFV and DCV prevented virus-induced neuronal apoptosis and release of cytokine storm-related inflammatory mediators, respectively. Both drugs inhibited independent events during RNA synthesis and this was particularly the case for DCV, which also targeted secondary RNA structures in the SARS-CoV-2 genome. Concentrations required for partial DCV in vitro activity are achieved in plasma at Cmax after administration of the approved dose to humans. Doses higher than those approved may ultimately be required, but these data provide a basis to further explore these agents as COVID-19 antiviral candidates.Competing Interest StatementThe authors have declared no competing interest.