The <i>in vitro</i> antiviral activity of the anti-hepatitis C virus (HCV) drugs daclatasvir and sofosbuvir against SARS-CoV-2

Sacramento, Carolina Q.; Fintelman-Rodrigues, Natália; Temerozo, Jairo R.; Silva, Aline de Paula Dias da; Dias, Suelen da Silva Gomes; Silva, Carine dos Santos da; Ferreira, André C.; Mattos, Mayara; Pão, Camila R. R.; Freitas, Caroline de; Soares, Vinícius Cardoso; Hoelz, Lucas Villas Bôas; Fernandes, Tácio Vinício Amorim; Branco, Frederico Silva Castelo; Bastos, Mônica M.; Boechat, Núbia; Saraiva, Felipe B.; Ferreira, Marcelo Alves; Rajoli, Rajith K. R.; Pedrosa, Carolina da S. G.; Vitória, Gabriela; Souza, Letícia R. Q.; Goto‐Silva, Livia; Guimarães, Marília Zaluar P.; Rehen, Stevens; Owen, Andrew; Bozza, Fernando A.; Bou-Habib, Dumith Chequer; Bozza, Patrı́cia T.; Souza, Thiago Moreno L.

doi:10.1101/2020.06.15.153411

Cited by 41 publications

(62 citation statements)

References 42 publications

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“…Sacramento et al demonstrated that Sofosbuvir inhibited SARS-CoV-2 replication in human hepatoma-derived (Huh-2) and Type II pneumocyte-derived (Calu-3) cells with EC50 values of 6.2 and 9.5 µM, respectively. 4 Mesci et al showed that Sofosbuvir could protect human brain organoids from SARS-CoV-2 infection. 5 Considering its low toxicity, its ability to be rapidly activated to the triphosphate form by cellular enzymes, and the high intracellular stability of this active molecule, Sayad et al initiated a COVID-19 treatment clinical trial with Sofosbuvir and Velpatasvir, which together form the combination HCV drug EPCLUSA.…”

Section: Resultsmentioning

confidence: 99%

“…37 Daclatasvir was also shown to reduce SARS-CoV-2-induced enhancement of TNF-α and IL-6, key contributors to the cytokine storm, observed in some COVID-19 patients. 4 Because Velpatasvir and Daclatasvir share very similar core structures and target the same NS5A protein in HCV, and Daclatasvir has also been shown to inhibit SARS-CoV-2 replication 4 and is currently in COVID-19 clinical trial, 7 it is plausible that Velpatasvir and other drugs in this class, such as Ledipasvir, 38 Elbasvir, 39 Ombitasvir 40 and Pibrentasvir, 41 will display similar inhibitory activity for SARS-CoV-2.…”

Section: Resultsmentioning

confidence: 99%

“…21 By comparing the RNA genomes of HCV and SARS-CoV-2, Buonaguro et al suggested that Sofosbuvir might be an optimal nucleotide analogue to repurpose for COVID-19 treatment. 22 Other investigators have since demonstrated the ability of Sofosbuvir to inhibit SARS-CoV-2 replication in lung and brain cells, 4,5 and COVID-19 clinical trials with EPCLUSA 6 and with Sofosbuvir plus Daclatasvir 7 have been initiated in several countries. Recently, Sadeghi et al reported encouraging results from a clinical trial using Sofosbuvir (SOF) and Daclatasvir (DCV) as a potential combination treatment for moderate or severe COVID-19 patients.…”

Section: Introductionmentioning

confidence: 99%

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Sofosbuvir Terminated RNA is More Resistant to SARS-CoV-2 Proofreader than RNA Terminated by Remdesivir

Jockusch

Tao

et al. 2020

Preprint

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SARS-CoV-2 is responsible for COVID-19, resulting in the largest pandemic in over a hundred years. After examining the molecular structures and activities of hepatitis C viral inhibitors and comparing hepatitis C virus and coronavirus replication, we previously postulated that the FDA-approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) might inhibit SARS-CoV-2. We subsequently demonstrated that Sofosbuvir triphosphate is incorporated by the relatively low fidelity SARS-CoV and SARS-CoV-2 RNA-dependent RNA polymerases (RdRps), serving as an immediate polymerase reaction terminator, but not by a host-like high fidelity DNA polymerase. Other investigators have since demonstrated the ability of Sofosbuvir to inhibit SARS-CoV-2 replication in lung and brain cells; additionally, COVID-19 clinical trials with EPCLUSA and with Sofosbuvir plus Daclatasvir have been initiated in several countries. SARS-CoV-2 has an exonuclease-based proofreader to maintain the viral genome integrity. Any effective antiviral targeting the SARS-CoV-2 RdRp must display a certain level of resistance to this proofreading activity. We report here that Sofosbuvir terminated RNA resists removal by the exonuclease to a substantially higher extent than RNA terminated by Remdesivir, another drug being used as a COVID-19 therapeutic. These results offer a molecular basis supporting the current use of Sofosbuvir in combination with other drugs in COVID-19 clinical trials.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sofosbuvir Terminated RNA is More Resistant to SARS-CoV-2 Proofreader than RNA Terminated by Remdesivir

Jockusch

Tao

et al. 2020

Preprint

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“…Sofosbuvir has been shown to inhibit SARS-CoV-2 replication in Huh-2 (human hepatoma-derived) and Calu-3 (Type II pneumocyte-derived) cells with EC50 values of 6.2 and 9.5 μM, respectively, but not in Vero-E6 cells. 32 Sofosbuvir was also shown to protect human brain organoids from infection by SARS-CoV-2. 33 A recent preprint provides K 1/2 values (the concentration leading to 50% SARS-CoV-2 polymerase extension) for a library of nucleotide analogues including Sofosbuvir and others examined in this paper.…”

Section: Note Added In Revisionmentioning

confidence: 99%

Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase, a Key Drug Target for COVID-19

et al. 2020

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SARS-CoV-2 is responsible for the current COVID-19 pandemic. On the basis of our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously demonstrated that three nucleotide analogues (the triphosphates of Sofosbuvir, Alovudine, and AZT) inhibit the SARS-CoV RNA-dependent RNA polymerase (RdRp). We also demonstrated that a library of additional nucleotide analogues terminate RNA synthesis catalyzed by the SARS-CoV-2 RdRp, a well-established drug target for COVID-19. Here, we used polymerase extension experiments to demonstrate that the active triphosphate form of Sofosbuvir (an FDA-approved hepatitis C drug) is incorporated by SARS-CoV-2 RdRp and blocks further incorporation. Using the molecular insight gained from the previous studies, we selected the active triphosphate forms of six other antiviral agents, Alovudine, Tenofovir alafenamide, AZT, Abacavir, Lamivudine, and Emtricitabine, for evaluation as inhibitors of the SARS-CoV-2 RdRp and demonstrated the ability of these viral polymerase inhibitors to be incorporated by SARS-CoV-2 RdRp, where they terminate further polymerase extension with varying efficiency. These results provide a molecular basis for inhibition of the SARS-CoV-2 RdRp by these nucleotide analogues. If sufficient efficacy of some of these FDA-approved drugs in inhibiting viral replication in cell culture is established, they may be explored as potential COVID-19 therapeutics.

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“…It has been found in recent studies that drugs currently used to treat hepatitis C inhibited the replication of the novel coronavirus in experiments conducted in vitro. These experiments considered the potential of antiviral activity of remdesivir (RDV), simeprevir (SPV), sofosbuvir (SFV), and daclatasvir (DCV) anti-HCV therapy against SARS-CoV-2 (Chien et al, 2020;Li et al, 2020;Lo et al, 2020;Sacramento et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Anti-HCV antiviral therapies as an alternative for the treatment of Covid-19

Medeiros

Farias

et al. 2020

RSD

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The current pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread alarmingly around the world at a significantly faster speed than previous coronaviral outbreaks. Due to the lack of a vaccine at the moment, an early antiviral intervention can prevent the spread of the disease worldwide and improve the clinical results of infected patients. The SARS-CoV-2 virus and the Hepatitis C virus (HCV) have a similar structure, replication, and catalytic mechanisms, therefore, several studies have considered the potential for antiviral activity of anti-HCV drugs such as remdesivir, simeprevir, sofosbuvir, and daclatasvir against SARS-CoV-2. Therefore, the present study aims to evaluate and discuss the antivirals already available against HCV, which have also been shown to be potential inhibitors of SARS-CoV-2 replication. The study was based on a literature review, of a qualitative nature and an exploratory type. Studies with anti-HCV drugs are promising and are already considered to start clinical trials in patients infected with the new coronavirus, having been observed as inhibitors of SARS-CoV-2 viral replication. Thus, the present study brings a pharmaco-clinical review on antivirals remdesivir, simeprevir, sofosbuvir, and daclatasvir, considering the main studies carried out to date in the treatment for Covid-19.

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The in vitro antiviral activity of the anti-hepatitis C virus (HCV) drugs daclatasvir and sofosbuvir against SARS-CoV-2

Cited by 41 publications

References 42 publications

Sofosbuvir Terminated RNA is More Resistant to SARS-CoV-2 Proofreader than RNA Terminated by Remdesivir

Sofosbuvir Terminated RNA is More Resistant to SARS-CoV-2 Proofreader than RNA Terminated by Remdesivir

Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase, a Key Drug Target for COVID-19

Anti-HCV antiviral therapies as an alternative for the treatment of Covid-19

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