Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease
Identifieur interne : 001236 ( Pmc/Curation ); précédent : 001235; suivant : 001237Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease
Auteurs : Maria L. Agostini [États-Unis] ; Erica L. Andres [États-Unis] ; Amy C. Sims [États-Unis] ; Rachel L. Graham [États-Unis] ; Timothy P. Sheahan [États-Unis] ; Xiaotao Lu [États-Unis] ; Everett Clinton Smith [États-Unis] ; James Brett Case [États-Unis] ; Joy Y. Feng [États-Unis] ; Robert Jordan [États-Unis] ; Adrian S. Ray [États-Unis] ; Tomas Cihlar [États-Unis] ; Dustin Siegel [États-Unis] ; Richard L. Mackman [États-Unis] ; Michael O. Clarke [États-Unis] ; Ralph S. Baric [États-Unis] ; Mark R. Denison [États-Unis]Source :
- mBio [ 2150-7511 ] ; 2018.
Abstract
Emerging coronaviruses (CoVs) cause severe disease in humans, but no approved therapeutics are available. The CoV nsp14 exoribonuclease (ExoN) has complicated development of antiviral nucleosides due to its proofreading activity. We recently reported that the nucleoside analogue GS-5734 (remdesivir) potently inhibits human and zoonotic CoVs
Url:
DOI: 10.1128/mBio.00221-18
PubMed: 29511076
PubMed Central: 5844999
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<author><name sortKey="Agostini, Maria L" sort="Agostini, Maria L" uniqKey="Agostini M" first="Maria L." last="Agostini">Maria L. Agostini</name>
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<author><name sortKey="Smith, Everett Clinton" sort="Smith, Everett Clinton" uniqKey="Smith E" first="Everett Clinton" last="Smith">Everett Clinton Smith</name>
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<author><name sortKey="Case, James Brett" sort="Case, James Brett" uniqKey="Case J" first="James Brett" last="Case">James Brett Case</name>
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<author><name sortKey="Feng, Joy Y" sort="Feng, Joy Y" uniqKey="Feng J" first="Joy Y." last="Feng">Joy Y. Feng</name>
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<author><name sortKey="Jordan, Robert" sort="Jordan, Robert" uniqKey="Jordan R" first="Robert" last="Jordan">Robert Jordan</name>
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<author><name sortKey="Cihlar, Tomas" sort="Cihlar, Tomas" uniqKey="Cihlar T" first="Tomas" last="Cihlar">Tomas Cihlar</name>
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</nlm:aff>
<country xml:lang="fr">États-Unis</country>
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<author><name sortKey="Siegel, Dustin" sort="Siegel, Dustin" uniqKey="Siegel D" first="Dustin" last="Siegel">Dustin Siegel</name>
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</nlm:aff>
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<author><name sortKey="Mackman, Richard L" sort="Mackman, Richard L" uniqKey="Mackman R" first="Richard L." last="Mackman">Richard L. Mackman</name>
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<author><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name>
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</nlm:aff>
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</nlm:aff>
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</nlm:aff>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease</title>
<author><name sortKey="Agostini, Maria L" sort="Agostini, Maria L" uniqKey="Agostini M" first="Maria L." last="Agostini">Maria L. Agostini</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Andres, Erica L" sort="Andres, Erica L" uniqKey="Andres E" first="Erica L." last="Andres">Erica L. Andres</name>
<affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee</wicri:regionArea>
</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="1"><nlm:aff id="aff3"><addr-line>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea>
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<author><name sortKey="Graham, Rachel L" sort="Graham, Rachel L" uniqKey="Graham R" first="Rachel L." last="Graham">Rachel L. Graham</name>
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</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea>
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<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="1"><nlm:aff id="aff3"><addr-line>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea>
</affiliation>
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<author><name sortKey="Lu, Xiaotao" sort="Lu, Xiaotao" uniqKey="Lu X" first="Xiaotao" last="Lu">Xiaotao Lu</name>
<affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Smith, Everett Clinton" sort="Smith, Everett Clinton" uniqKey="Smith E" first="Everett Clinton" last="Smith">Everett Clinton Smith</name>
<affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Department of Biology, the University of the South, Sewanee, Tennessee, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biology, the University of the South, Sewanee, Tennessee</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Case, James Brett" sort="Case, James Brett" uniqKey="Case J" first="James Brett" last="Case">James Brett Case</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee</wicri:regionArea>
</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="1"><nlm:aff id="aff5"><addr-line>Gilead Sciences, Inc., Foster City, California, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Gilead Sciences, Inc., Foster City, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Jordan, Robert" sort="Jordan, Robert" uniqKey="Jordan R" first="Robert" last="Jordan">Robert Jordan</name>
<affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>Gilead Sciences, Inc., Foster City, California, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Gilead Sciences, Inc., Foster City, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ray, Adrian S" sort="Ray, Adrian S" uniqKey="Ray A" first="Adrian S." last="Ray">Adrian S. Ray</name>
<affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>Gilead Sciences, Inc., Foster City, California, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Gilead Sciences, Inc., Foster City, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Cihlar, Tomas" sort="Cihlar, Tomas" uniqKey="Cihlar T" first="Tomas" last="Cihlar">Tomas Cihlar</name>
<affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>Gilead Sciences, Inc., Foster City, California, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Gilead Sciences, Inc., Foster City, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Siegel, Dustin" sort="Siegel, Dustin" uniqKey="Siegel D" first="Dustin" last="Siegel">Dustin Siegel</name>
<affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>Gilead Sciences, Inc., Foster City, California, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Gilead Sciences, Inc., Foster City, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mackman, Richard L" sort="Mackman, Richard L" uniqKey="Mackman R" first="Richard L." last="Mackman">Richard L. Mackman</name>
<affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>Gilead Sciences, Inc., Foster City, California, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Gilead Sciences, Inc., Foster City, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Clarke, Michael O" sort="Clarke, Michael O" uniqKey="Clarke M" first="Michael O." last="Clarke">Michael O. Clarke</name>
<affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>Gilead Sciences, Inc., Foster City, California, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Gilead Sciences, Inc., Foster City, California</wicri:regionArea>
</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="1"><nlm:aff id="aff3"><addr-line>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea>
</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="1"><nlm:aff id="aff1"><addr-line>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">mBio</title>
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<imprint><date when="2018">2018</date>
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<front><div type="abstract" xml:lang="en"><title>ABSTRACT</title>
<p>Emerging coronaviruses (CoVs) cause severe disease in humans, but no approved therapeutics are available. The CoV nsp14 exoribonuclease (ExoN) has complicated development of antiviral nucleosides due to its proofreading activity. We recently reported that the nucleoside analogue GS-5734 (remdesivir) potently inhibits human and zoonotic CoVs <italic>in vitro</italic>
and in a severe acute respiratory syndrome coronavirus (SARS-CoV) mouse model. However, studies with GS-5734 have not reported resistance associated with GS-5734, nor do we understand the action of GS-5734 in wild-type (WT) proofreading CoVs. Here, we show that GS-5734 inhibits murine hepatitis virus (MHV) with similar 50% effective concentration values (EC<sub>50</sub>
) as SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Passage of WT MHV in the presence of the GS-5734 parent nucleoside selected two mutations in the nsp12 polymerase at residues conserved across all CoVs that conferred up to 5.6-fold resistance to GS-5734, as determined by EC<sub>50</sub>
. The resistant viruses were unable to compete with WT in direct coinfection passage in the absence of GS-5734. Introduction of the MHV resistance mutations into SARS-CoV resulted in the same <italic>in vitro</italic>
resistance phenotype and attenuated SARS-CoV pathogenesis in a mouse model. Finally, we demonstrate that an MHV mutant lacking ExoN proofreading was significantly more sensitive to GS-5734. Combined, the results indicate that GS-5734 interferes with the nsp12 polymerase even in the setting of intact ExoN proofreading activity and that resistance can be overcome with increased, nontoxic concentrations of GS-5734, further supporting the development of GS-5734 as a broad-spectrum therapeutic to protect against contemporary and emerging CoVs.</p>
</div>
</front>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">mBio</journal-id>
<journal-id journal-id-type="iso-abbrev">MBio</journal-id>
<journal-id journal-id-type="hwp">mbio</journal-id>
<journal-id journal-id-type="pmc">mbio</journal-id>
<journal-id journal-id-type="publisher-id">mBio</journal-id>
<journal-title-group><journal-title>mBio</journal-title>
</journal-title-group>
<issn pub-type="epub">2150-7511</issn>
<publisher><publisher-name>American Society for Microbiology</publisher-name>
<publisher-loc>1752 N St., N.W., Washington, DC</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">29511076</article-id>
<article-id pub-id-type="pmc">5844999</article-id>
<article-id pub-id-type="publisher-id">mBio00221-18</article-id>
<article-id pub-id-type="doi">10.1128/mBio.00221-18</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease</article-title>
<alt-title alt-title-type="running-head">Coronavirus Inhibition by Remdesivir (GS-5734)</alt-title>
<alt-title alt-title-type="short-authors">Agostini et al.</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Agostini</surname>
<given-names>Maria L.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Andres</surname>
<given-names>Erica L.</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="no"><name><surname>Sims</surname>
<given-names>Amy C.</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>c</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="no"><name><surname>Graham</surname>
<given-names>Rachel L.</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>c</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="no"><name><surname>Sheahan</surname>
<given-names>Timothy P.</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>c</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="no"><name><surname>Lu</surname>
<given-names>Xiaotao</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="no"><name><surname>Smith</surname>
<given-names>Everett Clinton</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
<xref ref-type="aff" rid="aff4"><sup>d</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="no"><name><surname>Case</surname>
<given-names>James Brett</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="no"><name><surname>Feng</surname>
<given-names>Joy Y.</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>e</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="no"><name><surname>Jordan</surname>
<given-names>Robert</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>e</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="no"><name><surname>Ray</surname>
<given-names>Adrian S.</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>e</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="no"><name><surname>Cihlar</surname>
<given-names>Tomas</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>e</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="no"><name><surname>Siegel</surname>
<given-names>Dustin</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>e</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="no"><name><surname>Mackman</surname>
<given-names>Richard L.</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>e</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="no"><name><surname>Clarke</surname>
<given-names>Michael O.</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>e</sup>
</xref>
</contrib>
<contrib contrib-type="author" corresp="yes" equal-contrib="no"><name><surname>Baric</surname>
<given-names>Ralph S.</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>c</sup>
</xref>
</contrib>
<contrib contrib-type="author" corresp="yes" equal-contrib="no"><name><surname>Denison</surname>
<given-names>Mark R.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<aff id="aff1"><label>a</label>
<addr-line>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line>
</aff>
<aff id="aff2"><label>b</label>
<addr-line>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line>
</aff>
<aff id="aff3"><label>c</label>
<addr-line>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA</addr-line>
</aff>
<aff id="aff4"><label>d</label>
<addr-line>Department of Biology, the University of the South, Sewanee, Tennessee, USA</addr-line>
</aff>
<aff id="aff5"><label>e</label>
<addr-line>Gilead Sciences, Inc., Foster City, California, USA</addr-line>
</aff>
</contrib-group>
<contrib-group><contrib contrib-type="editor"><name><surname>Subbarao</surname>
<given-names>Kanta</given-names>
</name>
<role>Editor</role>
<aff>NIAID, NIH</aff>
</contrib>
</contrib-group>
<author-notes><corresp id="cor1">Address correspondence to Ralph S. Baric, <email>rbaric@email.unc.edu</email>
, or Mark R. Denison, <email>mark.denison@vanderbilt.edu</email>
.</corresp>
<fn fn-type="equal"><p>M.L.A. and E.L.A. contributed equally to this article.</p>
</fn>
<fn fn-type="other"><p>This article is a direct contribution from a Fellow of the American Academy of Microbiology. Solicited external reviewers: Tom Gallagher, Loyola University Medical Center; Luis Enjuanes, Centro Nacional de Biotecnologia, CNB-CSIC.</p>
</fn>
</author-notes>
<pub-date pub-type="epub"><day>6</day>
<month>3</month>
<year>2018</year>
</pub-date>
<pub-date pub-type="collection"><season>Mar-Apr</season>
<year>2018</year>
</pub-date>
<volume>9</volume>
<issue>2</issue>
<elocation-id>e00221-18</elocation-id>
<history><date date-type="received"><day>29</day>
<month>1</month>
<year>2018</year>
</date>
<date date-type="accepted"><day>1</day>
<month>2</month>
<year>2018</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2018 Agostini et al.</copyright-statement>
<copyright-year>2018</copyright-year>
<copyright-holder>Agostini et al.</copyright-holder>
<license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution 4.0 International license</ext-link>
.</license-p>
</license>
</permissions>
<self-uri content-type="pdf" xlink:href="mbo002183762001.pdf"></self-uri>
<abstract><title>ABSTRACT</title>
<p>Emerging coronaviruses (CoVs) cause severe disease in humans, but no approved therapeutics are available. The CoV nsp14 exoribonuclease (ExoN) has complicated development of antiviral nucleosides due to its proofreading activity. We recently reported that the nucleoside analogue GS-5734 (remdesivir) potently inhibits human and zoonotic CoVs <italic>in vitro</italic>
and in a severe acute respiratory syndrome coronavirus (SARS-CoV) mouse model. However, studies with GS-5734 have not reported resistance associated with GS-5734, nor do we understand the action of GS-5734 in wild-type (WT) proofreading CoVs. Here, we show that GS-5734 inhibits murine hepatitis virus (MHV) with similar 50% effective concentration values (EC<sub>50</sub>
) as SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Passage of WT MHV in the presence of the GS-5734 parent nucleoside selected two mutations in the nsp12 polymerase at residues conserved across all CoVs that conferred up to 5.6-fold resistance to GS-5734, as determined by EC<sub>50</sub>
. The resistant viruses were unable to compete with WT in direct coinfection passage in the absence of GS-5734. Introduction of the MHV resistance mutations into SARS-CoV resulted in the same <italic>in vitro</italic>
resistance phenotype and attenuated SARS-CoV pathogenesis in a mouse model. Finally, we demonstrate that an MHV mutant lacking ExoN proofreading was significantly more sensitive to GS-5734. Combined, the results indicate that GS-5734 interferes with the nsp12 polymerase even in the setting of intact ExoN proofreading activity and that resistance can be overcome with increased, nontoxic concentrations of GS-5734, further supporting the development of GS-5734 as a broad-spectrum therapeutic to protect against contemporary and emerging CoVs.</p>
</abstract>
<abstract abstract-type="executive-summary"><title>IMPORTANCE</title>
<p>Coronaviruses (CoVs) cause severe human infections, but there are no approved antivirals to treat these infections. Development of nucleoside-based therapeutics for CoV infections has been hampered by the presence of a proofreading exoribonuclease. Here, we expand the known efficacy of the nucleotide prodrug remdesivir (GS-5734) to include a group β-2a CoV. Further, GS-5734 potently inhibits CoVs with intact proofreading. Following selection with the GS-5734 parent nucleoside, 2 amino acid substitutions in the nsp12 polymerase at residues that are identical across CoVs provide low-level resistance to GS-5734. The resistance mutations decrease viral fitness of MHV <italic>in vitro</italic>
and attenuate pathogenesis in a SARS-CoV animal model of infection. Together, these studies define the target of GS-5734 activity and demonstrate that resistance is difficult to select, only partial, and impairs fitness and virulence of MHV and SARS-CoV, supporting further development of GS-5734 as a potential effective pan-CoV antiviral.</p>
</abstract>
<kwd-group><title>KEYWORDS</title>
<kwd>RNA polymerases</kwd>
<kwd>SARS-CoV</kwd>
<kwd>antiviral agents</kwd>
<kwd>antiviral resistance</kwd>
<kwd>coronavirus</kwd>
<kwd>nucleoside analogs</kwd>
<kwd>pandemic</kwd>
</kwd-group>
<funding-group><award-group id="award1"><funding-source><institution-wrap><institution>National Institutes of Health (NIH)</institution>
<institution-id>https://doi.org/10.13039/100000002</institution-id>
</institution-wrap>
</funding-source>
<award-id>5T32AI089554</award-id>
<principal-award-recipient><name><surname>Agostini</surname>
<given-names>Maria L.</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award2"><funding-source><institution-wrap><institution>National Institutes of Health (NIH)</institution>
<institution-id>https://doi.org/10.13039/100000002</institution-id>
</institution-wrap>
</funding-source>
<award-id>5U19AI109680</award-id>
<principal-award-recipient><name><surname>Baric</surname>
<given-names>Ralph S.</given-names>
</name>
</principal-award-recipient>
<principal-award-recipient><name><surname>Denison</surname>
<given-names>Mark R.</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award3"><funding-source><institution-wrap><institution>Cystic Fibrosis and Pulmonary Research and Treatment Center</institution>
</institution-wrap>
</funding-source>
<award-id>BOUCHE15RO</award-id>
<principal-award-recipient><name><surname>Baric</surname>
<given-names>Ralph S.</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award4"><funding-source><institution-wrap><institution>HHS | National Institutes of Health (NIH)</institution>
<institution-id>https://doi.org/10.13039/100000002</institution-id>
</institution-wrap>
</funding-source>
<award-id>R01AI108197</award-id>
<principal-award-recipient><name><surname>Denison</surname>
<given-names>Mark R.</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award5"><funding-source><institution-wrap><institution>HHS | National Institutes of Health (NIH)</institution>
<institution-id>https://doi.org/10.13039/100000002</institution-id>
</institution-wrap>
</funding-source>
<award-id>P30DK065988</award-id>
<principal-award-recipient><name><surname>Baric</surname>
<given-names>Ralph S.</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<counts><fig-count count="7"></fig-count>
<table-count count="2"></table-count>
<equation-count count="0"></equation-count>
<ref-count count="58"></ref-count>
<page-count count="15"></page-count>
<word-count count="10232"></word-count>
</counts>
<custom-meta-group><custom-meta><meta-name>cover-date</meta-name>
<meta-value>March/April 2018</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
</pmc>
</record>
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