Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase
Identifieur interne : 000484 ( Pmc/Checkpoint ); précédent : 000483; suivant : 000485Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase
Auteurs : Ariane J. Brown [États-Unis] ; John J. Won [États-Unis] ; Rachel L. Graham [États-Unis] ; Kenneth H. Dinnon [États-Unis] ; Amy C. Sims [États-Unis] ; Joy Y. Feng [États-Unis] ; Tomas Cihlar [États-Unis] ; Mark R. Denison [États-Unis] ; Ralph S. Baric [États-Unis] ; Timothy P. Sheahan [États-Unis]Source :
- Antiviral Research [ 0166-3542 ] ; 2019.
Abstract
The genetically diverse
Url:
DOI: 10.1016/j.antiviral.2019.104541
PubMed: 31233808
PubMed Central: 6699884
Affiliations:
- États-Unis
- Californie, Caroline du Nord, Tennessee
- Chapel Hill (Caroline du Nord)
- Université de Caroline du Nord à Chapel Hill
Links toward previous steps (curation, corpus...)
Links to Exploration step
PMC:6699884Le document en format XML
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Brown</name><affiliation wicri:level="4"><nlm:aff id="aff1">Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC</wicri:regionArea><placeName><region type="state">Caroline du Nord</region><settlement type="city">Chapel Hill (Caroline du Nord)</settlement></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></affiliation></author><author><name sortKey="Won, John J" sort="Won, John J" uniqKey="Won J" first="John J." last="Won">John J. 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Denison</name><affiliation wicri:level="2"><nlm:aff id="aff3">Department of Pediatrics-Infectious Diseases, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics-Infectious Diseases, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. 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Brown</name><affiliation wicri:level="4"><nlm:aff id="aff1">Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC</wicri:regionArea><placeName><region type="state">Caroline du Nord</region><settlement type="city">Chapel Hill (Caroline du Nord)</settlement></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></affiliation></author><author><name sortKey="Won, John J" sort="Won, John J" uniqKey="Won J" first="John J." last="Won">John J. Won</name><affiliation wicri:level="4"><nlm:aff id="aff1">Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC</wicri:regionArea><placeName><region type="state">Caroline du Nord</region><settlement type="city">Chapel Hill (Caroline du Nord)</settlement></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></affiliation></author><author><name sortKey="Graham, Rachel L" sort="Graham, Rachel L" uniqKey="Graham R" first="Rachel L." last="Graham">Rachel L. Graham</name><affiliation wicri:level="4"><nlm:aff id="aff1">Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC</wicri:regionArea><placeName><region type="state">Caroline du Nord</region><settlement type="city">Chapel Hill (Caroline du Nord)</settlement></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></affiliation></author><author><name sortKey="Dinnon, Kenneth H" sort="Dinnon, Kenneth H" uniqKey="Dinnon K" first="Kenneth H." last="Dinnon">Kenneth H. Dinnon</name><affiliation wicri:level="4"><nlm:aff id="aff1">Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC</wicri:regionArea><placeName><region type="state">Caroline du Nord</region><settlement type="city">Chapel Hill (Caroline du Nord)</settlement></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></affiliation></author><author><name sortKey="Sims, Amy C" sort="Sims, Amy C" uniqKey="Sims A" first="Amy C." last="Sims">Amy C. Sims</name><affiliation wicri:level="4"><nlm:aff id="aff1">Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC</wicri:regionArea><placeName><region type="state">Caroline du Nord</region><settlement type="city">Chapel Hill (Caroline du Nord)</settlement></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></affiliation></author><author><name sortKey="Feng, Joy Y" sort="Feng, Joy Y" uniqKey="Feng J" first="Joy Y." last="Feng">Joy Y. Feng</name><affiliation wicri:level="2"><nlm:aff id="aff2">Gilead Sciences, Inc., Foster City, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Gilead Sciences, Inc., Foster City, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Cihlar, Tomas" sort="Cihlar, Tomas" uniqKey="Cihlar T" first="Tomas" last="Cihlar">Tomas Cihlar</name><affiliation wicri:level="2"><nlm:aff id="aff2">Gilead Sciences, Inc., Foster City, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Gilead Sciences, Inc., Foster City, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Denison, Mark R" sort="Denison, Mark R" uniqKey="Denison M" first="Mark R." last="Denison">Mark R. Denison</name><affiliation wicri:level="2"><nlm:aff id="aff3">Department of Pediatrics-Infectious Diseases, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics-Infectious Diseases, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name><affiliation wicri:level="4"><nlm:aff id="aff1">Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC</wicri:regionArea><placeName><region type="state">Caroline du Nord</region><settlement type="city">Chapel Hill (Caroline du Nord)</settlement></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></affiliation></author><author><name sortKey="Sheahan, Timothy P" sort="Sheahan, Timothy P" uniqKey="Sheahan T" first="Timothy P." last="Sheahan">Timothy P. Sheahan</name><affiliation wicri:level="4"><nlm:aff id="aff1">Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC</wicri:regionArea><placeName><region type="state">Caroline du Nord</region><settlement type="city">Chapel Hill (Caroline du Nord)</settlement></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></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="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The genetically diverse <italic>Orthocoronavirinae</italic> (CoV) family is prone to cross species transmission and disease emergence in both humans and livestock. Viruses similar to known epidemic strains circulating in wild and domestic animals further increase the probability of emergence in the future. Currently, there are no approved therapeutics for any human CoV presenting a clear unmet medical need. Remdesivir (RDV, GS-5734) is a monophosphoramidate prodrug of an adenosine analog with potent activity against an array of RNA virus families including <italic>Filoviridae</italic>, <italic>Paramyxoviridae</italic>, <italic>Pneumoviridae</italic>, and <italic>Orthocoronavirinae</italic>, through the targeting of the viral RNA dependent RNA polymerase (RdRp). We developed multiple assays to further define the breadth of RDV antiviral activity against the CoV family. Here, we show potent antiviral activity of RDV against endemic human CoVs OC43 (HCoV-OC43) and 229E (HCoV-229E) with submicromolar EC<sub>50</sub> values. Of known CoVs, the members of the <italic>deltacoronavirus</italic> genus have the most divergent RdRp as compared to SARS- and MERS-CoV and both avian and porcine members harbor a native residue in the RdRp that confers resistance in beta-CoVs. Nevertheless, RDV is highly efficacious against porcine deltacoronavirus (PDCoV). These data further extend the known breadth and antiviral activity of RDV to include both contemporary human and highly divergent zoonotic CoV and potentially enhance our ability to fight future emerging CoV.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Agostini, M L" uniqKey="Agostini M">M.L. Agostini</name></author><author><name sortKey="Andres, E L" uniqKey="Andres E">E.L. Andres</name></author><author><name sortKey="Sims, A C" uniqKey="Sims A">A.C. Sims</name></author><author><name sortKey="Graham, R L" uniqKey="Graham R">R.L. 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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">31233808</article-id><article-id pub-id-type="pmc">6699884</article-id><article-id pub-id-type="publisher-id">S0166-3542(19)30099-3</article-id><article-id pub-id-type="doi">10.1016/j.antiviral.2019.104541</article-id><article-id pub-id-type="publisher-id">104541</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase</article-title></title-group><contrib-group><contrib contrib-type="author" id="au1"><name><surname>Brown</surname><given-names>Ariane J.</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au2"><name><surname>Won</surname><given-names>John J.</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au3"><name><surname>Graham</surname><given-names>Rachel L.</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au4"><name><surname>Dinnon</surname><given-names>Kenneth H.</given-names><suffix>III</suffix></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au5"><name><surname>Sims</surname><given-names>Amy C.</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au6"><name><surname>Feng</surname><given-names>Joy Y.</given-names></name><xref rid="aff2" ref-type="aff">b</xref></contrib><contrib contrib-type="author" id="au7"><name><surname>Cihlar</surname><given-names>Tomas</given-names></name><xref rid="aff2" ref-type="aff">b</xref></contrib><contrib contrib-type="author" id="au8"><name><surname>Denison</surname><given-names>Mark R.</given-names></name><xref rid="aff3" ref-type="aff">c</xref></contrib><contrib contrib-type="author" id="au9"><name><surname>Baric</surname><given-names>Ralph S.</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au10"><name><surname>Sheahan</surname><given-names>Timothy P.</given-names></name><email>sheahan@email.unc.edu</email><xref rid="aff1" ref-type="aff">a</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib></contrib-group><aff id="aff1"><label>a</label>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA</aff><aff id="aff2"><label>b</label>Gilead Sciences, Inc., Foster City, CA, USA</aff><aff id="aff3"><label>c</label>Department of Pediatrics-Infectious Diseases, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, NC, 27599, USA. <email>sheahan@email.unc.edu</email></corresp></author-notes><pub-date pub-type="pmc-release"><day>21</day><month>6</month><year>2019</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>9</month><year>2019</year></pub-date><pub-date pub-type="epub"><day>21</day><month>6</month><year>2019</year></pub-date><volume>169</volume><fpage>104541</fpage><lpage>104541</lpage><history><date date-type="received"><day>20</day><month>2</month><year>2019</year></date><date date-type="rev-recd"><day>18</day><month>6</month><year>2019</year></date><date date-type="accepted"><day>19</day><month>6</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 Elsevier B.V. All rights reserved.</copyright-statement><copyright-year>2019</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>The genetically diverse <italic>Orthocoronavirinae</italic> (CoV) family is prone to cross species transmission and disease emergence in both humans and livestock. Viruses similar to known epidemic strains circulating in wild and domestic animals further increase the probability of emergence in the future. Currently, there are no approved therapeutics for any human CoV presenting a clear unmet medical need. Remdesivir (RDV, GS-5734) is a monophosphoramidate prodrug of an adenosine analog with potent activity against an array of RNA virus families including <italic>Filoviridae</italic>, <italic>Paramyxoviridae</italic>, <italic>Pneumoviridae</italic>, and <italic>Orthocoronavirinae</italic>, through the targeting of the viral RNA dependent RNA polymerase (RdRp). We developed multiple assays to further define the breadth of RDV antiviral activity against the CoV family. Here, we show potent antiviral activity of RDV against endemic human CoVs OC43 (HCoV-OC43) and 229E (HCoV-229E) with submicromolar EC<sub>50</sub> values. Of known CoVs, the members of the <italic>deltacoronavirus</italic> genus have the most divergent RdRp as compared to SARS- and MERS-CoV and both avian and porcine members harbor a native residue in the RdRp that confers resistance in beta-CoVs. Nevertheless, RDV is highly efficacious against porcine deltacoronavirus (PDCoV). These data further extend the known breadth and antiviral activity of RDV to include both contemporary human and highly divergent zoonotic CoV and potentially enhance our ability to fight future emerging CoV.</p></abstract><abstract abstract-type="author-highlights" id="abs0015"><title>Highlights</title><p><list list-type="simple" id="ulist0010"><list-item id="u0010"><label>•</label><p id="p0010">In vitro antiviral assays were developed for human CoV OC43 and 229E and the zoonotic PDCoV.</p></list-item><list-item id="u0015"><label>•</label><p id="p0015">The nucleoside analog RDV inhibited HCoV-OC43 and 229E as well as deltacoronavirus member PDCoV.</p></list-item><list-item id="u0020"><label>•</label><p id="p0020">RDV has broad-spectrum antiviral activity against CoV and should be evaluated for future emerging CoV.</p></list-item></list></p></abstract><kwd-group id="kwrds0010"><title>Keywords</title><kwd>Coronavirus</kwd><kwd>Emerging viruses</kwd><kwd>Broad-spectrum antivirals</kwd><kwd>GS-5743</kwd><kwd>Remdesivir</kwd></kwd-group><kwd-group id="kwrds0015"><title>Abbreviations</title><kwd>CoV, <italic>Orthocoronavirinae</italic></kwd><kwd>HCoV-OC43, Human coronavirus OC43</kwd><kwd>HCoV-229E, Human coronavirus 229E</kwd><kwd>PDCoV, Porcine deltacoronavirus</kwd><kwd>Remdesivir (GS-5734), RDV</kwd><kwd>RdRp, RNA dependent RNA polymerase</kwd></kwd-group></article-meta></front></pmc><affiliations><list><country><li>États-Unis</li></country><region><li>Californie</li><li>Caroline du Nord</li><li>Tennessee</li></region><settlement><li>Chapel Hill (Caroline du Nord)</li></settlement><orgName><li>Université de Caroline du Nord à Chapel Hill</li></orgName></list><tree><country name="États-Unis"><region name="Caroline du Nord"><name sortKey="Brown, Ariane J" sort="Brown, Ariane J" uniqKey="Brown A" first="Ariane J." last="Brown">Ariane J. Brown</name></region><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name><name sortKey="Cihlar, Tomas" sort="Cihlar, Tomas" uniqKey="Cihlar T" first="Tomas" last="Cihlar">Tomas Cihlar</name><name sortKey="Denison, Mark R" sort="Denison, Mark R" uniqKey="Denison M" first="Mark R." last="Denison">Mark R. Denison</name><name sortKey="Dinnon, Kenneth H" sort="Dinnon, Kenneth H" uniqKey="Dinnon K" first="Kenneth H." last="Dinnon">Kenneth H. Dinnon</name><name sortKey="Feng, Joy Y" sort="Feng, Joy Y" uniqKey="Feng J" first="Joy Y." last="Feng">Joy Y. Feng</name><name sortKey="Graham, Rachel L" sort="Graham, Rachel L" uniqKey="Graham R" first="Rachel L." last="Graham">Rachel L. Graham</name><name sortKey="Sheahan, Timothy P" sort="Sheahan, Timothy P" uniqKey="Sheahan T" first="Timothy P." last="Sheahan">Timothy P. Sheahan</name><name sortKey="Sims, Amy C" sort="Sims, Amy C" uniqKey="Sims A" first="Amy C." last="Sims">Amy C. Sims</name><name sortKey="Won, John J" sort="Won, John J" uniqKey="Won J" first="John J." last="Won">John J. Won</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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