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In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2.

Identifieur interne : 000D01 ( Main/Exploration ); précédent : 000D00; suivant : 000D02

In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2.

Auteurs : Andrés Pizzorno [France] ; Blandine Padey [France] ; Julia Dubois [France] ; Thomas Julien [France] ; Aurélien Traversier [France] ; Victoria Dulière [France] ; Pauline Brun [France] ; Bruno Lina [France] ; Manuel Rosa-Calatrava [France] ; Olivier Terrier [France]

Source :

RBID : pubmed:32679055

Descripteurs français

English descriptors

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.

DOI: 10.1016/j.antiviral.2020.104878
PubMed: 32679055
PubMed Central: PMC7361110


Affiliations:


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Le document en format XML

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<name sortKey="Terrier, Olivier" sort="Terrier, Olivier" uniqKey="Terrier O" first="Olivier" last="Terrier">Olivier Terrier</name>
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<wicri:regionArea>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</wicri:regionArea>
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<title level="j">Antiviral research</title>
<idno type="eISSN">1872-9096</idno>
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<date when="2020" type="published">2020</date>
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<keywords scheme="KwdEn" xml:lang="en">
<term>Adenosine Monophosphate (analogs & derivatives)</term>
<term>Adenosine Monophosphate (pharmacology)</term>
<term>Alanine (analogs & derivatives)</term>
<term>Alanine (pharmacology)</term>
<term>Animals (MeSH)</term>
<term>Antiviral Agents (pharmacology)</term>
<term>Berberine (pharmacology)</term>
<term>Betacoronavirus (drug effects)</term>
<term>Chlorocebus aethiops (MeSH)</term>
<term>Chloroquine (pharmacology)</term>
<term>Coronavirus Infections (drug therapy)</term>
<term>Coronavirus Infections (virology)</term>
<term>Cyclosporine (pharmacology)</term>
<term>Drug Antagonism (MeSH)</term>
<term>Drug Combinations (MeSH)</term>
<term>Drug Repositioning (MeSH)</term>
<term>Drug Synergism (MeSH)</term>
<term>Humans (MeSH)</term>
<term>Indoles (pharmacology)</term>
<term>Lopinavir (pharmacology)</term>
<term>Pandemics (MeSH)</term>
<term>Pneumonia, Viral (drug therapy)</term>
<term>Pneumonia, Viral (virology)</term>
<term>Vero Cells (MeSH)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr">
<term>AMP (analogues et dérivés)</term>
<term>AMP (pharmacologie)</term>
<term>Alanine (analogues et dérivés)</term>
<term>Alanine (pharmacologie)</term>
<term>Animaux (MeSH)</term>
<term>Antagonisme des médicaments (MeSH)</term>
<term>Antiviraux (pharmacologie)</term>
<term>Association médicamenteuse (MeSH)</term>
<term>Berbérine (pharmacologie)</term>
<term>Betacoronavirus (effets des médicaments et des substances chimiques)</term>
<term>Cellules Vero (MeSH)</term>
<term>Chloroquine (pharmacologie)</term>
<term>Ciclosporine (pharmacologie)</term>
<term>Humains (MeSH)</term>
<term>Indoles (pharmacologie)</term>
<term>Infections à coronavirus (traitement médicamenteux)</term>
<term>Infections à coronavirus (virologie)</term>
<term>Lopinavir (pharmacologie)</term>
<term>Pandémies (MeSH)</term>
<term>Pneumopathie virale (traitement médicamenteux)</term>
<term>Pneumopathie virale (virologie)</term>
<term>Repositionnement des médicaments (MeSH)</term>
<term>Synergie des médicaments (MeSH)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en">
<term>Adenosine Monophosphate</term>
<term>Alanine</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en">
<term>Adenosine Monophosphate</term>
<term>Alanine</term>
<term>Antiviral Agents</term>
<term>Berberine</term>
<term>Chloroquine</term>
<term>Cyclosporine</term>
<term>Indoles</term>
<term>Lopinavir</term>
</keywords>
<keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr">
<term>AMP</term>
<term>Alanine</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en">
<term>Betacoronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en">
<term>Coronavirus Infections</term>
<term>Pneumonia, Viral</term>
</keywords>
<keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr">
<term>Betacoronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr">
<term>AMP</term>
<term>Alanine</term>
<term>Antiviraux</term>
<term>Berbérine</term>
<term>Chloroquine</term>
<term>Ciclosporine</term>
<term>Indoles</term>
<term>Lopinavir</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr">
<term>Infections à coronavirus</term>
<term>Pneumopathie virale</term>
</keywords>
<keywords scheme="MESH" qualifier="virologie" xml:lang="fr">
<term>Infections à coronavirus</term>
<term>Pneumopathie virale</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en">
<term>Coronavirus Infections</term>
<term>Pneumonia, Viral</term>
</keywords>
<keywords scheme="MESH" xml:lang="en">
<term>Animals</term>
<term>Chlorocebus aethiops</term>
<term>Drug Antagonism</term>
<term>Drug Combinations</term>
<term>Drug Repositioning</term>
<term>Drug Synergism</term>
<term>Humans</term>
<term>Pandemics</term>
<term>Vero Cells</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr">
<term>Animaux</term>
<term>Antagonisme des médicaments</term>
<term>Association médicamenteuse</term>
<term>Cellules Vero</term>
<term>Humains</term>
<term>Pandémies</term>
<term>Repositionnement des médicaments</term>
<term>Synergie des médicaments</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">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.</div>
</front>
</TEI>
<pubmed>
<MedlineCitation Status="MEDLINE" Owner="NLM">
<PMID Version="1">32679055</PMID>
<DateCompleted>
<Year>2020</Year>
<Month>09</Month>
<Day>07</Day>
</DateCompleted>
<DateRevised>
<Year>2020</Year>
<Month>09</Month>
<Day>07</Day>
</DateRevised>
<Article PubModel="Print-Electronic">
<Journal>
<ISSN IssnType="Electronic">1872-9096</ISSN>
<JournalIssue CitedMedium="Internet">
<Volume>181</Volume>
<PubDate>
<Year>2020</Year>
<Month>09</Month>
</PubDate>
</JournalIssue>
<Title>Antiviral research</Title>
<ISOAbbreviation>Antiviral Res.</ISOAbbreviation>
</Journal>
<ArticleTitle>In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2.</ArticleTitle>
<Pagination>
<MedlinePgn>104878</MedlinePgn>
</Pagination>
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<ELocationID EIdType="doi" ValidYN="Y">10.1016/j.antiviral.2020.104878</ELocationID>
<Abstract>
<AbstractText>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.</AbstractText>
<CopyrightInformation>Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y">
<Author ValidYN="Y">
<LastName>Pizzorno</LastName>
<ForeName>Andrés</ForeName>
<Initials>A</Initials>
<AffiliationInfo>
<Affiliation>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.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Padey</LastName>
<ForeName>Blandine</ForeName>
<Initials>B</Initials>
<AffiliationInfo>
<Affiliation>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.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Dubois</LastName>
<ForeName>Julia</ForeName>
<Initials>J</Initials>
<AffiliationInfo>
<Affiliation>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.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Julien</LastName>
<ForeName>Thomas</ForeName>
<Initials>T</Initials>
<AffiliationInfo>
<Affiliation>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.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Traversier</LastName>
<ForeName>Aurélien</ForeName>
<Initials>A</Initials>
<AffiliationInfo>
<Affiliation>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.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Dulière</LastName>
<ForeName>Victoria</ForeName>
<Initials>V</Initials>
<AffiliationInfo>
<Affiliation>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.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Brun</LastName>
<ForeName>Pauline</ForeName>
<Initials>P</Initials>
<AffiliationInfo>
<Affiliation>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.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Lina</LastName>
<ForeName>Bruno</ForeName>
<Initials>B</Initials>
<AffiliationInfo>
<Affiliation>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.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Rosa-Calatrava</LastName>
<ForeName>Manuel</ForeName>
<Initials>M</Initials>
<AffiliationInfo>
<Affiliation>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.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Terrier</LastName>
<ForeName>Olivier</ForeName>
<Initials>O</Initials>
<AffiliationInfo>
<Affiliation>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.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<PublicationTypeList>
<PublicationType UI="D016428">Journal Article</PublicationType>
<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic">
<Year>2020</Year>
<Month>07</Month>
<Day>15</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo>
<Country>Netherlands</Country>
<MedlineTA>Antiviral Res</MedlineTA>
<NlmUniqueID>8109699</NlmUniqueID>
<ISSNLinking>0166-3542</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList>
<Chemical>
<RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000998">Antiviral Agents</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D004338">Drug Combinations</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D007211">Indoles</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>0I8Y3P32UF</RegistryNumber>
<NameOfSubstance UI="D001599">Berberine</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>2494G1JF75</RegistryNumber>
<NameOfSubstance UI="D061466">Lopinavir</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>3QKI37EEHE</RegistryNumber>
<NameOfSubstance UI="C000606551">remdesivir</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>415SHH325A</RegistryNumber>
<NameOfSubstance UI="D000249">Adenosine Monophosphate</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>83HN0GTJ6D</RegistryNumber>
<NameOfSubstance UI="D016572">Cyclosporine</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>886U3H6UFF</RegistryNumber>
<NameOfSubstance UI="D002738">Chloroquine</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>93M09WW4RU</RegistryNumber>
<NameOfSubstance UI="C086979">arbidol</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>OF5P57N2ZX</RegistryNumber>
<NameOfSubstance UI="D000409">Alanine</NameOfSubstance>
</Chemical>
</ChemicalList>
<SupplMeshList>
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<SupplMeshName Type="Protocol" UI="C000705127">COVID-19 drug treatment</SupplMeshName>
<SupplMeshName Type="Organism" UI="C000656484">severe acute respiratory syndrome coronavirus 2</SupplMeshName>
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<MeshHeading>
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<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D000409" MajorTopicYN="N">Alanine</DescriptorName>
<QualifierName UI="Q000031" MajorTopicYN="N">analogs & derivatives</QualifierName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D000998" MajorTopicYN="N">Antiviral Agents</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D001599" MajorTopicYN="N">Berberine</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D000073640" MajorTopicYN="N">Betacoronavirus</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName>
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<MeshHeading>
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</MeshHeading>
<MeshHeading>
<DescriptorName UI="D002738" MajorTopicYN="N">Chloroquine</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D018352" MajorTopicYN="N">Coronavirus Infections</DescriptorName>
<QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName>
<QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D016572" MajorTopicYN="N">Cyclosporine</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D004336" MajorTopicYN="N">Drug Antagonism</DescriptorName>
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<MeshHeading>
<DescriptorName UI="D004338" MajorTopicYN="N">Drug Combinations</DescriptorName>
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<MeshHeading>
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<MeshHeading>
<DescriptorName UI="D007211" MajorTopicYN="N">Indoles</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D061466" MajorTopicYN="N">Lopinavir</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D058873" MajorTopicYN="Y">Pandemics</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D011024" MajorTopicYN="N">Pneumonia, Viral</DescriptorName>
<QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName>
<QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D014709" MajorTopicYN="N">Vero Cells</DescriptorName>
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</MeshHeadingList>
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<Keyword MajorTopicYN="Y">Berberine</Keyword>
<Keyword MajorTopicYN="Y">COVID-19</Keyword>
<Keyword MajorTopicYN="Y">Diltiazem</Keyword>
<Keyword MajorTopicYN="Y">Drug combination</Keyword>
<Keyword MajorTopicYN="Y">Remdesivir</Keyword>
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</MedlineCitation>
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<Month>05</Month>
<Day>06</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="revised">
<Year>2020</Year>
<Month>07</Month>
<Day>06</Day>
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<Month>07</Month>
<Day>07</Day>
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</country>
<region>
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<tree>
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<name sortKey="Duliere, Victoria" sort="Duliere, Victoria" uniqKey="Duliere V" first="Victoria" last="Dulière">Victoria Dulière</name>
<name sortKey="Julien, Thomas" sort="Julien, Thomas" uniqKey="Julien T" first="Thomas" last="Julien">Thomas Julien</name>
<name sortKey="Lina, Bruno" sort="Lina, Bruno" uniqKey="Lina B" first="Bruno" last="Lina">Bruno Lina</name>
<name sortKey="Padey, Blandine" sort="Padey, Blandine" uniqKey="Padey B" first="Blandine" last="Padey">Blandine Padey</name>
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