Broad-spectrum antiviral activity of the eIF4A inhibitor silvestrol against corona- and picornaviruses
Identifieur interne : 000A64 ( Pmc/Curation ); précédent : 000A63; suivant : 000A65Broad-spectrum antiviral activity of the eIF4A inhibitor silvestrol against corona- and picornaviruses
Auteurs : Christin Müller [Allemagne] ; Falk W. Schulte [Allemagne] ; Kerstin Lange-Grünweller [Allemagne] ; Wiebke Obermann [Allemagne] ; Ramakanth Madhugiri [Allemagne] ; Stephan Pleschka [Allemagne] ; John Ziebuhr [Allemagne] ; Roland K. Hartmann [Allemagne] ; Arnold Grünweller [Allemagne]Source :
- Antiviral Research [ 0166-3542 ] ; 2017.
Abstract
Coronaviruses (CoV) and picornaviruses are plus-strand RNA viruses that use 5′ cap-dependent and cap-independent strategies, respectively, for viral mRNA translation initiation. Here, we analyzed the effects of the plant compound silvestrol, a specific inhibitor of the DEAD-box RNA helicase eIF4A, on viral translation using a dual luciferase assay and virus-infected primary cells. Silvestrol was recently shown to have potent antiviral activity in Ebola virus-infected human macrophages. We found that silvestrol is also a potent inhibitor of cap-dependent viral mRNA translation in CoV-infected human embryonic lung fibroblast (MRC-5) cells. EC50 values of 1.3 nM and 3 nM silvestrol were determined for MERS-CoV and HCoV-229E, respectively. For the highly pathogenic MERS-CoV, the potent antiviral activities of silvestrol were also confirmed using peripheral blood mononuclear cells (PBMCs) as a second type of human primary cells. Silvestrol strongly inhibits the expression of CoV structural and nonstructural proteins (N, nsp8) and the formation of viral replication/transcription complexes. Furthermore, potential antiviral effects against human rhinovirus (HRV) A1 and poliovirus type 1 (PV), representing different species in the genus
Url:
DOI: 10.1016/j.antiviral.2017.12.010
PubMed: 29258862
PubMed Central: 7113723
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Hartmann</name><affiliation wicri:level="1"><nlm:aff id="aff2">Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg</wicri:regionArea></affiliation></author><author><name sortKey="Grunweller, Arnold" sort="Grunweller, Arnold" uniqKey="Grunweller A" first="Arnold" last="Grünweller">Arnold Grünweller</name><affiliation wicri:level="1"><nlm:aff id="aff2">Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">29258862</idno><idno type="pmc">7113723</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113723</idno><idno type="RBID">PMC:7113723</idno><idno type="doi">10.1016/j.antiviral.2017.12.010</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">000A64</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A64</idno><idno type="wicri:Area/Pmc/Curation">000A64</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000A64</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Broad-spectrum antiviral activity of the eIF4A inhibitor silvestrol against corona- and picornaviruses</title><author><name sortKey="Muller, Christin" sort="Muller, Christin" uniqKey="Muller C" first="Christin" last="Müller">Christin Müller</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institut für Medizinische Virologie, Justus-Liebig-Universität Gießen, Schubertstraße 81, 35392 Gießen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institut für Medizinische Virologie, Justus-Liebig-Universität Gießen, Schubertstraße 81, 35392 Gießen</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3">Deutsches Zentrum für Infektionsforschung (DZIF) at the partner site Gießen-Marburg-Langen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Deutsches Zentrum für Infektionsforschung (DZIF) at the partner site Gießen-Marburg-Langen</wicri:regionArea></affiliation></author><author><name sortKey="Schulte, Falk W" sort="Schulte, Falk W" uniqKey="Schulte F" first="Falk W." last="Schulte">Falk W. Schulte</name><affiliation wicri:level="1"><nlm:aff id="aff2">Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg</wicri:regionArea></affiliation></author><author><name sortKey="Lange Grunweller, Kerstin" sort="Lange Grunweller, Kerstin" uniqKey="Lange Grunweller K" first="Kerstin" last="Lange-Grünweller">Kerstin Lange-Grünweller</name><affiliation wicri:level="1"><nlm:aff id="aff2">Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg</wicri:regionArea></affiliation></author><author><name sortKey="Obermann, Wiebke" sort="Obermann, Wiebke" uniqKey="Obermann W" first="Wiebke" last="Obermann">Wiebke Obermann</name><affiliation wicri:level="1"><nlm:aff id="aff2">Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg</wicri:regionArea></affiliation></author><author><name sortKey="Madhugiri, Ramakanth" sort="Madhugiri, Ramakanth" uniqKey="Madhugiri R" first="Ramakanth" last="Madhugiri">Ramakanth Madhugiri</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institut für Medizinische Virologie, Justus-Liebig-Universität Gießen, Schubertstraße 81, 35392 Gießen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institut für Medizinische Virologie, Justus-Liebig-Universität Gießen, Schubertstraße 81, 35392 Gießen</wicri:regionArea></affiliation></author><author><name sortKey="Pleschka, Stephan" sort="Pleschka, Stephan" uniqKey="Pleschka S" first="Stephan" last="Pleschka">Stephan Pleschka</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institut für Medizinische Virologie, Justus-Liebig-Universität Gießen, Schubertstraße 81, 35392 Gießen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institut für Medizinische Virologie, Justus-Liebig-Universität Gießen, Schubertstraße 81, 35392 Gießen</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3">Deutsches Zentrum für Infektionsforschung (DZIF) at the partner site Gießen-Marburg-Langen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Deutsches Zentrum für Infektionsforschung (DZIF) at the partner site Gießen-Marburg-Langen</wicri:regionArea></affiliation></author><author><name sortKey="Ziebuhr, John" sort="Ziebuhr, John" uniqKey="Ziebuhr J" first="John" last="Ziebuhr">John Ziebuhr</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institut für Medizinische Virologie, Justus-Liebig-Universität Gießen, Schubertstraße 81, 35392 Gießen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institut für Medizinische Virologie, Justus-Liebig-Universität Gießen, Schubertstraße 81, 35392 Gießen</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3">Deutsches Zentrum für Infektionsforschung (DZIF) at the partner site Gießen-Marburg-Langen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Deutsches Zentrum für Infektionsforschung (DZIF) at the partner site Gießen-Marburg-Langen</wicri:regionArea></affiliation></author><author><name sortKey="Hartmann, Roland K" sort="Hartmann, Roland K" uniqKey="Hartmann R" first="Roland K." last="Hartmann">Roland K. Hartmann</name><affiliation wicri:level="1"><nlm:aff id="aff2">Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg</wicri:regionArea></affiliation></author><author><name sortKey="Grunweller, Arnold" sort="Grunweller, Arnold" uniqKey="Grunweller A" first="Arnold" last="Grünweller">Arnold Grünweller</name><affiliation wicri:level="1"><nlm:aff id="aff2">Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg</wicri:regionArea></affiliation></author></analytic><series><title level="j">Antiviral Research</title><idno type="ISSN">0166-3542</idno><idno type="eISSN">1872-9096</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Coronaviruses (CoV) and picornaviruses are plus-strand RNA viruses that use 5′ cap-dependent and cap-independent strategies, respectively, for viral mRNA translation initiation. Here, we analyzed the effects of the plant compound silvestrol, a specific inhibitor of the DEAD-box RNA helicase eIF4A, on viral translation using a dual luciferase assay and virus-infected primary cells. Silvestrol was recently shown to have potent antiviral activity in Ebola virus-infected human macrophages. We found that silvestrol is also a potent inhibitor of cap-dependent viral mRNA translation in CoV-infected human embryonic lung fibroblast (MRC-5) cells. EC<sub>50</sub> values of 1.3 nM and 3 nM silvestrol were determined for MERS-CoV and HCoV-229E, respectively. For the highly pathogenic MERS-CoV, the potent antiviral activities of silvestrol were also confirmed using peripheral blood mononuclear cells (PBMCs) as a second type of human primary cells. Silvestrol strongly inhibits the expression of CoV structural and nonstructural proteins (N, nsp8) and the formation of viral replication/transcription complexes. Furthermore, potential antiviral effects against human rhinovirus (HRV) A1 and poliovirus type 1 (PV), representing different species in the genus <italic>Enterovirus</italic> (family <italic>Picornaviridae</italic>), were investigated. The two viruses employ an internal ribosomal entry site (IRES)-mediated translation initiation mechanism. For PV, which is known to require the activity of eIF4A, an EC<sub>50</sub> value of 20 nM silvestrol was determined in MRC-5 cells. The higher EC<sub>50</sub> value of 100 nM measured for HRV A1 indicates a less critical role of eIF4A activity in HRV A1 IRES-mediated translation initiation. Taken together, the data reveal a broad-spectrum antiviral activity of silvestrol in infected primary cells by inhibiting eIF4A-dependent viral mRNA translation.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Biedenkopf, N" uniqKey="Biedenkopf N">N. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Antiviral Res</journal-id><journal-id journal-id-type="iso-abbrev">Antiviral Res</journal-id><journal-title-group><journal-title>Antiviral Research</journal-title></journal-title-group><issn pub-type="ppub">0166-3542</issn><issn pub-type="epub">1872-9096</issn><publisher><publisher-name>Elsevier B.V.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">29258862</article-id><article-id pub-id-type="pmc">7113723</article-id><article-id pub-id-type="publisher-id">S0166-3542(17)30638-1</article-id><article-id pub-id-type="doi">10.1016/j.antiviral.2017.12.010</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Broad-spectrum antiviral activity of the eIF4A inhibitor silvestrol against corona- and picornaviruses</article-title></title-group><contrib-group><contrib contrib-type="author" id="au1"><name><surname>Müller</surname><given-names>Christin</given-names></name><xref rid="aff1" ref-type="aff">a</xref><xref rid="aff3" ref-type="aff">c</xref><xref rid="fn1" ref-type="fn">1</xref></contrib><contrib contrib-type="author" id="au2"><name><surname>Schulte</surname><given-names>Falk W.</given-names></name><xref rid="aff2" ref-type="aff">b</xref><xref rid="fn1" ref-type="fn">1</xref></contrib><contrib contrib-type="author" id="au3"><name><surname>Lange-Grünweller</surname><given-names>Kerstin</given-names></name><xref rid="aff2" ref-type="aff">b</xref></contrib><contrib contrib-type="author" id="au4"><name><surname>Obermann</surname><given-names>Wiebke</given-names></name><xref rid="aff2" ref-type="aff">b</xref></contrib><contrib contrib-type="author" id="au5"><name><surname>Madhugiri</surname><given-names>Ramakanth</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au6"><name><surname>Pleschka</surname><given-names>Stephan</given-names></name><xref rid="aff1" ref-type="aff">a</xref><xref rid="aff3" ref-type="aff">c</xref></contrib><contrib contrib-type="author" id="au7"><name><surname>Ziebuhr</surname><given-names>John</given-names></name><xref rid="aff1" ref-type="aff">a</xref><xref rid="aff3" ref-type="aff">c</xref></contrib><contrib contrib-type="author" id="au8"><name><surname>Hartmann</surname><given-names>Roland K.</given-names></name><xref rid="aff2" ref-type="aff">b</xref></contrib><contrib contrib-type="author" id="au9"><name><surname>Grünweller</surname><given-names>Arnold</given-names></name><email>gruenwel@staff.uni-marburg.de</email><xref rid="aff2" ref-type="aff">b</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib></contrib-group><aff id="aff1"><label>a</label>Institut für Medizinische Virologie, Justus-Liebig-Universität Gießen, Schubertstraße 81, 35392 Gießen, Germany</aff><aff id="aff2"><label>b</label>Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg, Germany</aff><aff id="aff3"><label>c</label>Deutsches Zentrum für Infektionsforschung (DZIF) at the partner site Gießen-Marburg-Langen, Germany</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author. <email>gruenwel@staff.uni-marburg.de</email></corresp><fn id="fn1"><label>1</label><p id="ntpara0010">Both authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="pmc-release"><day>16</day><month>12</month><year>2017</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="ppub"><month>2</month><year>2018</year></pub-date><pub-date pub-type="epub"><day>16</day><month>12</month><year>2017</year></pub-date><volume>150</volume><fpage>123</fpage><lpage>129</lpage><history><date date-type="received"><day>5</day><month>10</month><year>2017</year></date><date date-type="rev-recd"><day>12</day><month>12</month><year>2017</year></date><date date-type="accepted"><day>14</day><month>12</month><year>2017</year></date></history><permissions><copyright-statement>© 2017 Elsevier B.V. All rights reserved.</copyright-statement><copyright-year>2017</copyright-year><copyright-holder>Elsevier B.V.</copyright-holder><license><license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p></license></permissions><abstract id="abs0010"><p>Coronaviruses (CoV) and picornaviruses are plus-strand RNA viruses that use 5′ cap-dependent and cap-independent strategies, respectively, for viral mRNA translation initiation. Here, we analyzed the effects of the plant compound silvestrol, a specific inhibitor of the DEAD-box RNA helicase eIF4A, on viral translation using a dual luciferase assay and virus-infected primary cells. Silvestrol was recently shown to have potent antiviral activity in Ebola virus-infected human macrophages. We found that silvestrol is also a potent inhibitor of cap-dependent viral mRNA translation in CoV-infected human embryonic lung fibroblast (MRC-5) cells. EC<sub>50</sub> values of 1.3 nM and 3 nM silvestrol were determined for MERS-CoV and HCoV-229E, respectively. For the highly pathogenic MERS-CoV, the potent antiviral activities of silvestrol were also confirmed using peripheral blood mononuclear cells (PBMCs) as a second type of human primary cells. Silvestrol strongly inhibits the expression of CoV structural and nonstructural proteins (N, nsp8) and the formation of viral replication/transcription complexes. Furthermore, potential antiviral effects against human rhinovirus (HRV) A1 and poliovirus type 1 (PV), representing different species in the genus <italic>Enterovirus</italic> (family <italic>Picornaviridae</italic>), were investigated. The two viruses employ an internal ribosomal entry site (IRES)-mediated translation initiation mechanism. For PV, which is known to require the activity of eIF4A, an EC<sub>50</sub> value of 20 nM silvestrol was determined in MRC-5 cells. The higher EC<sub>50</sub> value of 100 nM measured for HRV A1 indicates a less critical role of eIF4A activity in HRV A1 IRES-mediated translation initiation. Taken together, the data reveal a broad-spectrum antiviral activity of silvestrol in infected primary cells by inhibiting eIF4A-dependent viral mRNA translation.</p></abstract><abstract abstract-type="graphical" id="abs0015"><title>Graphical abstract</title><p><fig id="undfig1" position="anchor"><alt-text id="alttext0010">Image 1</alt-text><graphic xlink:href="fx1_lrg"></graphic></fig></p></abstract><abstract abstract-type="author-highlights" id="abs0020"><title>Highlights</title><p><list list-type="simple" id="ulist0010"><list-item id="u0010"><label>•</label><p id="p0010">The eIF4A inhibitor silvestrol is a potent antiviral compound that inhibits the replication of coronaviruses.</p></list-item><list-item id="u0015"><label>•</label><p id="p0015">Silvestrol is also effective against picornaviruses with an eIF4A-dependent Type 1 IRES element.</p></list-item><list-item id="u0020"><label>•</label><p id="p0020">In primary cells silvestrol has potent antiviral activity and low toxicity.</p></list-item><list-item id="u0025"><label>•</label><p id="p0025">Targeting the host factor eIF4A is a promising broad-spectrum antiviral strategy.</p></list-item></list></p></abstract><kwd-group id="kwrds0010"><title>Keywords</title><kwd>Silvestrol</kwd><kwd>Coronavirus</kwd><kwd>Picornavirus</kwd><kwd>eIF4A</kwd><kwd>Cap-dependent translation</kwd><kwd>IRES</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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