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In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2.
Antiviral Res. 2020 09; 181:104878.AR

Abstract

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.

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Authors+Show Affiliations

Pizzorno A
CIRI, Centre International de Recherche en Infectiologie, (Team VirPath), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France.
Padey B
CIRI, Centre International de Recherche en Infectiologie, (Team VirPath), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France; Signia Therapeutics SAS, Lyon, France.
Dubois J
CIRI, Centre International de Recherche en Infectiologie, (Team VirPath), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France.
Julien T
CIRI, Centre International de Recherche en Infectiologie, (Team VirPath), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France; VirNext, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.
Traversier A
CIRI, Centre International de Recherche en Infectiologie, (Team VirPath), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France.
Dulière V
CIRI, Centre International de Recherche en Infectiologie, (Team VirPath), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France; VirNext, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.
Brun P
CIRI, Centre International de Recherche en Infectiologie, (Team VirPath), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France; VirNext, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.
Lina B
CIRI, Centre International de Recherche en Infectiologie, (Team VirPath), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France; Laboratoire de Virologie, Centre National de Référence des Virus Influenza Sud, Institut des Agents Infectieux, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon, France.
Rosa-Calatrava M
CIRI, Centre International de Recherche en Infectiologie, (Team VirPath), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France; VirNext, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France. Electronic address: manuel.rosa-calatrava@univ-lyon1.fr.
Terrier O
CIRI, Centre International de Recherche en Infectiologie, (Team VirPath), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France. Electronic address: olivier.terrier@univ-lyon1.fr.

MeSH

Adenosine MonophosphateAlanineAnimalsAntiviral AgentsBerberineBetacoronavirusCOVID-19Chlorocebus aethiopsChloroquineCoronavirus InfectionsCyclosporineDrug AntagonismDrug CombinationsDrug RepositioningDrug SynergismHumansIndolesLopinavirPandemicsPneumonia, ViralSARS-CoV-2Vero Cells

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32679055

Clinical Trial Links

Remdesivir- Ivermectin Combination Therapy in Severe Covid-19

Citation

Pizzorno, Andrés, et al. "In Vitro Evaluation of Antiviral Activity of Single and Combined Repurposable Drugs Against SARS-CoV-2." Antiviral Research, vol. 181, 2020, p. 104878.
Pizzorno A, Padey B, Dubois J, et al. In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2. Antiviral Res. 2020;181:104878.
Pizzorno, A., Padey, B., Dubois, J., Julien, T., Traversier, A., Dulière, V., Brun, P., Lina, B., Rosa-Calatrava, M., & Terrier, O. (2020). In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2. Antiviral Research, 181, 104878. https://doi.org/10.1016/j.antiviral.2020.104878
Pizzorno A, et al. In Vitro Evaluation of Antiviral Activity of Single and Combined Repurposable Drugs Against SARS-CoV-2. Antiviral Res. 2020;181:104878. PubMed PMID: 32679055.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2. AU - Pizzorno,Andrés, AU - Padey,Blandine, AU - Dubois,Julia, AU - Julien,Thomas, AU - Traversier,Aurélien, AU - Dulière,Victoria, AU - Brun,Pauline, AU - Lina,Bruno, AU - Rosa-Calatrava,Manuel, AU - Terrier,Olivier, Y1 - 2020/07/15/ PY - 2020/05/06/received PY - 2020/07/06/revised PY - 2020/07/07/accepted PY - 2020/7/18/pubmed PY - 2020/9/8/medline PY - 2020/7/18/entrez KW - Antivirals KW - Berberine KW - COVID-19 KW - Diltiazem KW - Drug combination KW - Remdesivir SP - 104878 EP - 104878 JF - Antiviral research JO - Antiviral Res VL - 181 N2 - 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. SN - 1872-9096 UR - https://www.unboundmedicine.com/medline/citation/32679055/In_vitro_evaluation_of_antiviral_activity_of_single_and_combined_repurposable_drugs_against_SARS_CoV_2_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0166-3542(20)30292-8 DB - PRIME DP - Unbound Medicine ER -