Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease
Identifieur interne : 000D01 ( Main/Exploration ); précédent : 000D00; suivant : 000D02Coronavirus 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.
Descripteurs français
- KwdFr :
- Alanine (analogues et dérivés), Alanine (pharmacologie), Animaux, Antiviraux (pharmacologie), Coronavirus (), Coronavirus (enzymologie), Exoribonucleases (), Exoribonucleases (génétique), Exoribonucleases (métabolisme), Mutation (génétique), Ribonucléotides (pharmacologie), Réplication virale (), Réplication virale (génétique), Souris, Virus du SRAS (), Virus du SRAS (génétique).
- MESH :
- analogues et dérivés : Alanine.
- enzymologie : Coronavirus.
- génétique : Exoribonucleases, Mutation, Réplication virale, Virus du SRAS.
- métabolisme : Exoribonucleases.
- pharmacologie : Alanine, Antiviraux, Ribonucléotides.
- Animaux, Coronavirus, Exoribonucleases, Réplication virale, Souris, Virus du SRAS.
English descriptors
- KwdEn :
- Alanine (analogs & derivatives), Alanine (pharmacology), Animals, Antiviral Agents (pharmacology), Coronavirus (drug effects), Coronavirus (enzymology), Exoribonucleases (chemistry), Exoribonucleases (genetics), Exoribonucleases (metabolism), Mice, Mutation (genetics), Ribonucleotides (pharmacology), SARS Virus (drug effects), SARS Virus (genetics), Virus Replication (drug effects), Virus Replication (genetics).
- MESH :
- chemical , analogs & derivatives : Alanine.
- chemical , chemistry : Exoribonucleases.
- chemical , genetics : Exoribonucleases.
- chemical , metabolism : Exoribonucleases.
- chemical , pharmacology : Alanine, Antiviral Agents, Ribonucleotides.
- drug effects : Coronavirus, SARS Virus, Virus Replication.
- enzymology : Coronavirus.
- genetics : Mutation, SARS Virus, Virus Replication.
- Animals, Mice.
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
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...)
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- to stream Ncbi, to step Checkpoint: 002F11
- to stream Main, to step Merge: 000D03
- to stream Main, to step Curation: 000D01
Le document en format XML
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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>
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</nlm:aff>
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</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Gilead Sciences, Inc., Foster City, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Siegel, Dustin" sort="Siegel, Dustin" uniqKey="Siegel D" first="Dustin" last="Siegel">Dustin Siegel</name>
<affiliation wicri:level="2"><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>
<placeName><region type="state">Californie</region>
</placeName>
</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="2"><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>
<placeName><region type="state">Californie</region>
</placeName>
</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="2"><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>
<placeName><region type="state">Californie</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="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>
<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="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="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>
<placeName><region type="state">Tennessee</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><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>
<placeName><region type="state">Tennessee</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">mBio</title>
<idno type="eISSN">2150-7511</idno>
<imprint><date when="2018">2018</date>
</imprint>
</series>
</biblStruct>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Alanine (analogs & derivatives)</term>
<term>Alanine (pharmacology)</term>
<term>Animals</term>
<term>Antiviral Agents (pharmacology)</term>
<term>Coronavirus (drug effects)</term>
<term>Coronavirus (enzymology)</term>
<term>Exoribonucleases (chemistry)</term>
<term>Exoribonucleases (genetics)</term>
<term>Exoribonucleases (metabolism)</term>
<term>Mice</term>
<term>Mutation (genetics)</term>
<term>Ribonucleotides (pharmacology)</term>
<term>SARS Virus (drug effects)</term>
<term>SARS Virus (genetics)</term>
<term>Virus Replication (drug effects)</term>
<term>Virus Replication (genetics)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Alanine (analogues et dérivés)</term>
<term>Alanine (pharmacologie)</term>
<term>Animaux</term>
<term>Antiviraux (pharmacologie)</term>
<term>Coronavirus ()</term>
<term>Coronavirus (enzymologie)</term>
<term>Exoribonucleases ()</term>
<term>Exoribonucleases (génétique)</term>
<term>Exoribonucleases (métabolisme)</term>
<term>Mutation (génétique)</term>
<term>Ribonucléotides (pharmacologie)</term>
<term>Réplication virale ()</term>
<term>Réplication virale (génétique)</term>
<term>Souris</term>
<term>Virus du SRAS ()</term>
<term>Virus du SRAS (génétique)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Alanine</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Exoribonucleases</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Exoribonucleases</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Exoribonucleases</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Alanine</term>
<term>Antiviral Agents</term>
<term>Ribonucleotides</term>
</keywords>
<keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>Alanine</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Coronavirus</term>
<term>SARS Virus</term>
<term>Virus Replication</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Coronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Coronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Mutation</term>
<term>SARS Virus</term>
<term>Virus Replication</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Exoribonucleases</term>
<term>Mutation</term>
<term>Réplication virale</term>
<term>Virus du SRAS</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Exoribonucleases</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Alanine</term>
<term>Antiviraux</term>
<term>Ribonucléotides</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Mice</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Coronavirus</term>
<term>Exoribonucleases</term>
<term>Réplication virale</term>
<term>Souris</term>
<term>Virus du SRAS</term>
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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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</TEI>
<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="Tennessee"><name sortKey="Agostini, Maria L" sort="Agostini, Maria L" uniqKey="Agostini M" first="Maria L." last="Agostini">Maria L. Agostini</name>
</region>
<name sortKey="Andres, Erica L" sort="Andres, Erica L" uniqKey="Andres E" first="Erica L." last="Andres">Erica L. Andres</name>
<name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name>
<name sortKey="Case, James Brett" sort="Case, James Brett" uniqKey="Case J" first="James Brett" last="Case">James Brett Case</name>
<name sortKey="Cihlar, Tomas" sort="Cihlar, Tomas" uniqKey="Cihlar T" first="Tomas" last="Cihlar">Tomas Cihlar</name>
<name sortKey="Clarke, Michael O" sort="Clarke, Michael O" uniqKey="Clarke M" first="Michael O." last="Clarke">Michael O. Clarke</name>
<name sortKey="Denison, Mark R" sort="Denison, Mark R" uniqKey="Denison M" first="Mark R." last="Denison">Mark R. Denison</name>
<name sortKey="Denison, Mark R" sort="Denison, Mark R" uniqKey="Denison M" first="Mark R." last="Denison">Mark R. Denison</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="Jordan, Robert" sort="Jordan, Robert" uniqKey="Jordan R" first="Robert" last="Jordan">Robert Jordan</name>
<name sortKey="Lu, Xiaotao" sort="Lu, Xiaotao" uniqKey="Lu X" first="Xiaotao" last="Lu">Xiaotao Lu</name>
<name sortKey="Mackman, Richard L" sort="Mackman, Richard L" uniqKey="Mackman R" first="Richard L." last="Mackman">Richard L. Mackman</name>
<name sortKey="Ray, Adrian S" sort="Ray, Adrian S" uniqKey="Ray A" first="Adrian S." last="Ray">Adrian S. Ray</name>
<name sortKey="Sheahan, Timothy P" sort="Sheahan, Timothy P" uniqKey="Sheahan T" first="Timothy P." last="Sheahan">Timothy P. Sheahan</name>
<name sortKey="Siegel, Dustin" sort="Siegel, Dustin" uniqKey="Siegel D" first="Dustin" last="Siegel">Dustin Siegel</name>
<name sortKey="Sims, Amy C" sort="Sims, Amy C" uniqKey="Sims A" first="Amy C." last="Sims">Amy C. Sims</name>
<name sortKey="Smith, Everett Clinton" sort="Smith, Everett Clinton" uniqKey="Smith E" first="Everett Clinton" last="Smith">Everett Clinton Smith</name>
<name sortKey="Smith, Everett Clinton" sort="Smith, Everett Clinton" uniqKey="Smith E" first="Everett Clinton" last="Smith">Everett Clinton Smith</name>
</country>
</tree>
</affiliations>
</record>
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