key: cord-277860-vzyrcmu4
authors: Pizzorno, Andrés; Padey, Blandine; Dubois, Julia; Julien, Thomas; Traversier, Aurélien; Dulière, Victoria; Brun, Pauline; Lina, Bruno; Rosa-Calatrava, Manuel; Terrier, Olivier
title: In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2
date: 2020-07-15
journal: Antiviral Res
DOI: 10.1016/j.antiviral.2020.104878
sha: 
doc_id: 277860
cord_uid: vzyrcmu4

In response to the current pandemic caused by the novel SARS-CoV-2, identifying and validating effective therapeutic strategies is more than ever necessary. We evaluated the in vitro antiviral activities of a shortlist of compounds, known for their cellular broad-spectrum activities, together with drugs that are currently under evaluation in clinical trials for COVID-19 patients. We report the antiviral effect of remdesivir, lopinavir, chloroquine, umifenovir, berberine and cyclosporine A in Vero E6 cells model of SARS-CoV-2 infection, with estimated 50% inhibitory concentrations of 0.99, 5.2, 1.38, 3.5, 10.6 and 3 μM, respectively. Virus-directed plus host-directed drug combinations were also investigated. We report a strong antagonism between remdesivir and berberine, in contrast with remdesivir/diltiazem, for which we describe high levels of synergy, with mean Loewe synergy scores of 12 and peak values above 50. Combination of host-directed drugs with direct acting antivirals underscore further validation in more physiological models, yet they open up interesting avenues for the treatment of COVID-19.

In vitro evaluation of antiviral activity of single and combined repurposable drugs 1 against SARS-CoV-2 2 3 Authors: Andrés Pizzorno a , Blandine Padey a,b , Julia Dubois a , Thomas Julien a,c , Aurélien 4 Traversier a , Victoria Dulière a,c , Pauline Brun a,c , Bruno Lina a,d , Manuel Rosa-Calatrava a,c* † , 5 Olivier Terrier a* † 6 7 Author affiliations: Abstract: 27 In response to the current pandemic caused by the novel SARS-CoV-2, identifying and 28 validating effective therapeutic strategies is more than ever necessary. We evaluated the in 29 vitro antiviral activities of a shortlist of compounds, known for their cellular broad-spectrum 30 activities, together with drugs that are currently under evaluation in clinical trials for COVID-31 19 patients. We report the antiviral effect of remdesivir, lopinavir, chloroquine, umifenovir, 32 berberine and cyclosporine A in Vero E6 cells model of SARS-CoV-2 infection, with 33 estimated 50% inhibitory concentrations of 0.99, 5.2, 1.38, 3.5, 10.6 and 3 µM, respectively. 34 Virus-directed plus host-directed drug combinations were also investigated. We report a 35 strong antagonism between remdesivir and berberine, in contrast with remdesivir/diltiazem, 36 for which we describe high levels of synergy, with mean Loewe synergy scores of 12 and Table 2) . A similar trend was 146 observed when we analyzed the berberine dose-response profile in the presence of 0.625 µM 147 remdesivir but not at higher remdesivir concentrations (Figure 2A , right panel and Table 2 ). 148 To further explore this combination, we used SynergyFinder 

Targeting endosomal acidification by chloroquine analogs as a promising 197 strategy for the treatment of emerging viral diseases

Arbidol as a broad-spectrum antiviral: An update

A Trial of Lopinavir-Ritonavir in 208 Adults Hospitalized with Severe Covid-19

Favipiravir versus Arbidol for COVID-19: A 212 Randomized Clinical Trial

Zhang, Zhan, 2020. 215 Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical 216 trial

Remdesivir, lopinavir, 219 emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro

Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical 222 findings

The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen

Cyclosporin A inhibits the replication of diverse 229 coronaviruses

Antiviral combinations for severe influenza

Favipiravir (T-233 705), a novel viral RNA polymerase inhibitor

Vitro and In Vivo Activities of

Anti-Influenza Virus Compound T-705

Arbidol (Umifenovir): A Broad-Spectrum Antiviral Drug That Inhibits Medically 241 Important Arthropod-Borne Flaviviruses

Clinical features of 245 patients infected with 2019 novel coronavirus in Wuhan

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The effect of Arbidol Hydrochloride on reducing mortality 252 of Covid-19 patients: a retrospective study of real world date from three hospitals in Wuhan

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A Novel 309 Coronavirus from Patients with Pneumonia in China

In response to the current pandemic caused by the novel SARS-CoV-2, identifying and validating effective therapeutic strategies is more than ever necessary

We evaluated the in vitro antiviral activities of a shortlist of compounds, known for their cellular broad-spectrum activities, together with drugs that are currently under clinical evaluation

We report the antiviral effect of remdesivir, lopinavir, chloroquine, umifenovir, berberine and cyclosporine A in Vero E6 cells

We report a strong antagonism between remdesivir and berberine, in contrast with remdesivir/diltiazem, for which we describe high levels of synergy

Combinations of host-directed drugs with direct acting antivirals open interesting avenues for the treatment of COVID-19