PT  - JOURNAL ARTICLE
AU  - Carolina Q. Sacramento
AU  - Natalia Fintelman-Rodrigues
AU  - Jairo R. Temerozo
AU  - Aline de Paula Dias Da Silva
AU  - Suelen da Silva Gomes Dias
AU  - Carine dos Santos da Silva
AU  - André C. Ferreira
AU  - Mayara Mattos
AU  - Camila R. R. Pão
AU  - Caroline S. de Freitas
AU  - Vinicius Cardoso Soares
AU  - Lucas Villas Bôas Hoelz
AU  - Tácio Vinício Amorim Fernandes
AU  - Frederico Silva Castelo Branco
AU  - Mônica Macedo Bastos
AU  - Núbia Boechat
AU  - Felipe B. Saraiva
AU  - Marcelo Alves Ferreira
AU  - Rajith K. R. Rajoli
AU  - Carolina S. G. Pedrosa
AU  - Gabriela Vitória
AU  - Letícia R. Q. Souza
AU  - Livia Goto-Silva
AU  - Marilia Zaluar Guimarães
AU  - Stevens K. Rehen
AU  - Andrew Owen
AU  - Fernando A. Bozza
AU  - Dumith Chequer Bou-Habib
AU  - Patrícia T. Bozza
AU  - Thiago Moreno L. Souza
TI  - The <em>in vitro</em> antiviral activity of the anti-hepatitis C virus (HCV) drugs daclatasvir and sofosbuvir against SARS-CoV-2
AID  - 10.1101/2020.06.15.153411
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.15.153411
4099  - http://biorxiv.org/content/early/2020/10/16/2020.06.15.153411.short
4100  - http://biorxiv.org/content/early/2020/10/16/2020.06.15.153411.full
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.