Targeting Membrane-Bound Viral RNA Synthesis Reveals Potent Inhibition of Diverse Coronaviruses Including the Middle East Respiratory Syndrome Virus
Identifieur interne : 001A62 ( Main/Exploration ); précédent : 001A61; suivant : 001A63Targeting Membrane-Bound Viral RNA Synthesis Reveals Potent Inhibition of Diverse Coronaviruses Including the Middle East Respiratory Syndrome Virus
Auteurs : Anna Lundin [Suède] ; Ronald Dijkman [Suisse] ; Tomas Bergström [Suède] ; Nina Kann [Suède] ; Beata Adamiak [Suède] ; Charles Hannoun [Suède] ; Eveline Kindler [Suisse] ; Hulda R. J Nsd Ttir [Suisse] ; Doreen Muth [Allemagne] ; Joeri Kint [Pays-Bas] ; Maria Forlenza [Pays-Bas] ; Marcel A. Müller [Allemagne] ; Christian Drosten [Allemagne] ; Volker Thiel [Suisse] ; Edward Trybala [Suède]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2014.
Descripteurs français
- KwdFr :
- MESH :
- génétique : ARN viral.
- métabolisme : Membrane cellulaire.
- pharmacologie : Antiviraux.
- virologie : Infections à coronavirus.
- Animaux, Coronavirus, Humains, Infections à coronavirus, Lignée cellulaire, Pénétration virale, Réplication virale, Virus respiratoires syncytiaux.
English descriptors
- KwdEn :
- Animals, Antiviral Agents (pharmacology), Cell Line, Cell Membrane (metabolism), Coronavirus, Coronavirus Infections (prevention & control), Coronavirus Infections (virology), Humans, RNA, Viral (genetics), Respiratory Syncytial Viruses, Virus Internalization (drug effects), Virus Replication (drug effects).
- MESH :
- chemical , genetics : RNA, Viral.
- chemical , pharmacology : Antiviral Agents.
- drug effects : Virus Internalization, Virus Replication.
- metabolism : Cell Membrane.
- prevention & control : Coronavirus Infections.
- virology : Coronavirus Infections.
- Animals, Cell Line, Coronavirus, Humans, Respiratory Syncytial Viruses.
Abstract
Coronaviruses raise serious concerns as emerging zoonotic viruses without specific antiviral drugs available. Here we screened a collection of 16671 diverse compounds for anti-human coronavirus 229E activity and identified an inhibitor, designated K22, that specifically targets membrane-bound coronaviral RNA synthesis. K22 exerts most potent antiviral activity after virus entry during an early step of the viral life cycle. Specifically, the formation of double membrane vesicles (DMVs), a hallmark of coronavirus replication, was greatly impaired upon K22 treatment accompanied by near-complete inhibition of viral RNA synthesis. K22-resistant viruses contained substitutions in non-structural protein 6 (nsp6), a membrane-spanning integral component of the viral replication complex implicated in DMV formation, corroborating that K22 targets membrane bound viral RNA synthesis. Besides K22 resistance, the nsp6 mutants induced a reduced number of DMVs, displayed decreased specific infectivity, while RNA synthesis was not affected. Importantly, K22 inhibits a broad range of coronaviruses, including Middle East respiratory syndrome coronavirus (MERS–CoV), and efficient inhibition was achieved in primary human epithelia cultures representing the entry port of human coronavirus infection. Collectively, this study proposes an evolutionary conserved step in the life cycle of positive-stranded RNA viruses, the recruitment of cellular membranes for viral replication, as vulnerable and, most importantly, druggable target for antiviral intervention. We expect this mode of action to serve as a paradigm for the development of potent antiviral drugs to combat many animal and human virus infections.
Url:
DOI: 10.1371/journal.ppat.1004166
PubMed: 24874215
PubMed Central: 4038610
Affiliations:
- Allemagne, Pays-Bas, Suisse, Suède
- Canton de Berne, District de Cologne, Gueldre (province), Rhénanie-du-Nord-Westphalie
- Berne, Bonn, Wageningue
- Université de Wageningue
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Le document en format XML
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Mittelhäusern</wicri:regionArea><wicri:noRegion>Berne and Mittelhäusern</wicri:noRegion></affiliation><affiliation wicri:level="3"><nlm:aff id="aff8"><addr-line>Vetsuisse Faculty, University of Berne, Berne, Switzerland</addr-line></nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Vetsuisse Faculty, University of Berne, Berne</wicri:regionArea><placeName><settlement type="city">Berne</settlement><region type="région" nuts="3">Canton de Berne</region></placeName></affiliation></author><author><name sortKey="Trybala, Edward" sort="Trybala, Edward" uniqKey="Trybala E" first="Edward" last="Trybala">Edward Trybala</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Clinical Virology, University of Gothenburg, Göteborg, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Clinical Virology, University of Gothenburg, 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Virus</title><author><name sortKey="Lundin, Anna" sort="Lundin, Anna" uniqKey="Lundin A" first="Anna" last="Lundin">Anna Lundin</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Clinical Virology, University of Gothenburg, Göteborg, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Clinical Virology, University of Gothenburg, Göteborg</wicri:regionArea><wicri:noRegion>Göteborg</wicri:noRegion></affiliation></author><author><name sortKey="Dijkman, Ronald" sort="Dijkman, Ronald" uniqKey="Dijkman R" first="Ronald" last="Dijkman">Ronald Dijkman</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Immunobiology, Kantonal Hospital St.Gallen, St.Gallen, Switzerland</addr-line></nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Immunobiology, Kantonal Hospital St.Gallen, St.Gallen</wicri:regionArea><wicri:noRegion>St.Gallen</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern, Switzerland</addr-line></nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern</wicri:regionArea><wicri:noRegion>Berne and Mittelhäusern</wicri:noRegion></affiliation></author><author><name sortKey="Bergstrom, Tomas" sort="Bergstrom, Tomas" uniqKey="Bergstrom T" first="Tomas" last="Bergström">Tomas Bergström</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Clinical Virology, University of Gothenburg, Göteborg, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Clinical Virology, University of Gothenburg, Göteborg</wicri:regionArea><wicri:noRegion>Göteborg</wicri:noRegion></affiliation></author><author><name sortKey="Kann, Nina" sort="Kann, Nina" uniqKey="Kann N" first="Nina" last="Kann">Nina Kann</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Organic Chemistry, Department of Chemical and Biological Engineering, Chalmers University of Technology, Göteborg, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Organic Chemistry, Department of Chemical and Biological Engineering, Chalmers University of Technology, Göteborg</wicri:regionArea><wicri:noRegion>Göteborg</wicri:noRegion></affiliation></author><author><name sortKey="Adamiak, Beata" sort="Adamiak, Beata" uniqKey="Adamiak B" first="Beata" last="Adamiak">Beata Adamiak</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Clinical Virology, University of Gothenburg, Göteborg, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Clinical Virology, University of Gothenburg, Göteborg</wicri:regionArea><wicri:noRegion>Göteborg</wicri:noRegion></affiliation></author><author><name sortKey="Hannoun, Charles" sort="Hannoun, Charles" uniqKey="Hannoun C" first="Charles" last="Hannoun">Charles Hannoun</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Clinical Virology, University of Gothenburg, Göteborg, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Clinical Virology, University of Gothenburg, Göteborg</wicri:regionArea><wicri:noRegion>Göteborg</wicri:noRegion></affiliation></author><author><name sortKey="Kindler, Eveline" sort="Kindler, Eveline" uniqKey="Kindler E" first="Eveline" last="Kindler">Eveline Kindler</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Immunobiology, Kantonal Hospital St.Gallen, St.Gallen, Switzerland</addr-line></nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Immunobiology, Kantonal Hospital St.Gallen, St.Gallen</wicri:regionArea><wicri:noRegion>St.Gallen</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern, Switzerland</addr-line></nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern</wicri:regionArea><wicri:noRegion>Berne and Mittelhäusern</wicri:noRegion></affiliation></author><author><name sortKey="J Nsd Ttir, Hulda R" sort="J Nsd Ttir, Hulda R" uniqKey="J Nsd Ttir H" first="Hulda R." last="J Nsd Ttir">Hulda R. J Nsd Ttir</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Immunobiology, Kantonal Hospital St.Gallen, St.Gallen, Switzerland</addr-line></nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Immunobiology, Kantonal Hospital St.Gallen, St.Gallen</wicri:regionArea><wicri:noRegion>St.Gallen</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern, Switzerland</addr-line></nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern</wicri:regionArea><wicri:noRegion>Berne and Mittelhäusern</wicri:noRegion></affiliation></author><author><name sortKey="Muth, Doreen" sort="Muth, Doreen" uniqKey="Muth D" first="Doreen" last="Muth">Doreen Muth</name><affiliation wicri:level="3"><nlm:aff id="aff5"><addr-line>Institute of Virology, University of Bonn Medical Centre, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Bonn Medical Centre, Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Kint, Joeri" sort="Kint, Joeri" uniqKey="Kint J" first="Joeri" last="Kint">Joeri Kint</name><affiliation wicri:level="4"><nlm:aff id="aff6"><addr-line>Department of Animal Sciences, Cell Biology and Immunology Group, Wageningen Institute of Animal Sciences, Wageningen University, Wageningen, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Animal Sciences, Cell Biology and Immunology Group, Wageningen Institute of Animal Sciences, Wageningen University, Wageningen</wicri:regionArea><orgName type="university">Université de Wageningue</orgName><placeName><settlement type="city">Wageningue</settlement><region nuts="2">Gueldre (province)</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="aff7"><addr-line>Merck Animal Health, Bioprocess Technology & Support, Boxmeer, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Merck Animal Health, Bioprocess Technology & Support, Boxmeer</wicri:regionArea><wicri:noRegion>Boxmeer</wicri:noRegion></affiliation></author><author><name sortKey="Forlenza, Maria" sort="Forlenza, Maria" uniqKey="Forlenza M" first="Maria" last="Forlenza">Maria Forlenza</name><affiliation wicri:level="4"><nlm:aff id="aff6"><addr-line>Department of Animal Sciences, Cell Biology and Immunology Group, Wageningen Institute of Animal Sciences, Wageningen University, Wageningen, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Animal Sciences, Cell Biology and Immunology Group, Wageningen Institute of Animal Sciences, Wageningen University, Wageningen</wicri:regionArea><orgName type="university">Université de Wageningue</orgName><placeName><settlement type="city">Wageningue</settlement><region nuts="2">Gueldre (province)</region></placeName></affiliation></author><author><name sortKey="Muller, Marcel A" sort="Muller, Marcel A" uniqKey="Muller M" first="Marcel A." last="Müller">Marcel A. Müller</name><affiliation wicri:level="3"><nlm:aff id="aff5"><addr-line>Institute of Virology, University of Bonn Medical Centre, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Bonn Medical Centre, Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Drosten, Christian" sort="Drosten, Christian" uniqKey="Drosten C" first="Christian" last="Drosten">Christian Drosten</name><affiliation wicri:level="3"><nlm:aff id="aff5"><addr-line>Institute of Virology, University of Bonn Medical Centre, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Bonn Medical Centre, Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Thiel, Volker" sort="Thiel, Volker" uniqKey="Thiel V" first="Volker" last="Thiel">Volker Thiel</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Immunobiology, Kantonal Hospital St.Gallen, St.Gallen, Switzerland</addr-line></nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Immunobiology, Kantonal Hospital St.Gallen, St.Gallen</wicri:regionArea><wicri:noRegion>St.Gallen</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern, Switzerland</addr-line></nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern</wicri:regionArea><wicri:noRegion>Berne and Mittelhäusern</wicri:noRegion></affiliation><affiliation wicri:level="3"><nlm:aff id="aff8"><addr-line>Vetsuisse Faculty, University of Berne, Berne, Switzerland</addr-line></nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Vetsuisse Faculty, University of Berne, Berne</wicri:regionArea><placeName><settlement type="city">Berne</settlement><region type="région" nuts="3">Canton de Berne</region></placeName></affiliation></author><author><name sortKey="Trybala, Edward" sort="Trybala, Edward" uniqKey="Trybala E" first="Edward" last="Trybala">Edward Trybala</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Clinical Virology, University of Gothenburg, Göteborg, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Clinical Virology, University of Gothenburg, Göteborg</wicri:regionArea><wicri:noRegion>Göteborg</wicri:noRegion></affiliation></author></analytic><series><title level="j">PLoS Pathogens</title><idno type="ISSN">1553-7366</idno><idno type="eISSN">1553-7374</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antiviral Agents (pharmacology)</term><term>Cell Line</term><term>Cell Membrane (metabolism)</term><term>Coronavirus</term><term>Coronavirus Infections (prevention & control)</term><term>Coronavirus Infections (virology)</term><term>Humans</term><term>RNA, Viral (genetics)</term><term>Respiratory Syncytial Viruses</term><term>Virus Internalization (drug effects)</term><term>Virus Replication (drug effects)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>ARN viral (génétique)</term><term>Animaux</term><term>Antiviraux (pharmacologie)</term><term>Coronavirus</term><term>Humains</term><term>Infections à coronavirus ()</term><term>Infections à coronavirus (virologie)</term><term>Lignée cellulaire</term><term>Membrane cellulaire (métabolisme)</term><term>Pénétration virale ()</term><term>Réplication virale ()</term><term>Virus respiratoires syncytiaux</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>RNA, Viral</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Virus Internalization</term><term>Virus Replication</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>ARN viral</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Cell Membrane</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Membrane cellulaire</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term></keywords><keywords scheme="MESH" qualifier="prevention & control" xml:lang="en"><term>Coronavirus Infections</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Infections à coronavirus</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Coronavirus Infections</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line</term><term>Coronavirus</term><term>Humans</term><term>Respiratory Syncytial Viruses</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Coronavirus</term><term>Humains</term><term>Infections à coronavirus</term><term>Lignée cellulaire</term><term>Pénétration virale</term><term>Réplication virale</term><term>Virus respiratoires syncytiaux</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Coronaviruses raise serious concerns as emerging zoonotic viruses without specific antiviral drugs available. Here we screened a collection of 16671 diverse compounds for anti-human coronavirus 229E activity and identified an inhibitor, designated K22, that specifically targets membrane-bound coronaviral RNA synthesis. K22 exerts most potent antiviral activity after virus entry during an early step of the viral life cycle. Specifically, the formation of double membrane vesicles (DMVs), a hallmark of coronavirus replication, was greatly impaired upon K22 treatment accompanied by near-complete inhibition of viral RNA synthesis. K22-resistant viruses contained substitutions in non-structural protein 6 (nsp6), a membrane-spanning integral component of the viral replication complex implicated in DMV formation, corroborating that K22 targets membrane bound viral RNA synthesis. Besides K22 resistance, the nsp6 mutants induced a reduced number of DMVs, displayed decreased specific infectivity, while RNA synthesis was not affected. Importantly, K22 inhibits a broad range of coronaviruses, including Middle East respiratory syndrome coronavirus (MERS–CoV), and efficient inhibition was achieved in primary human epithelia cultures representing the entry port of human coronavirus infection. Collectively, this study proposes an evolutionary conserved step in the life cycle of positive-stranded RNA viruses, the recruitment of cellular membranes for viral replication, as vulnerable and, most importantly, druggable target for antiviral intervention. We expect this mode of action to serve as a paradigm for the development of potent antiviral drugs to combat many animal and human virus infections.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Drosten, C" uniqKey="Drosten C">C Drosten</name></author><author><name sortKey="Gunther, S" uniqKey="Gunther S">S Gunther</name></author><author><name sortKey="Preiser, W" uniqKey="Preiser W">W Preiser</name></author><author><name sortKey="Van Der Werf, S" uniqKey="Van Der Werf S">S van der Werf</name></author><author><name sortKey="Brodt, Hr" uniqKey="Brodt H">HR Brodt</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ksiazek, Tg" uniqKey="Ksiazek T">TG Ksiazek</name></author><author><name sortKey="Erdman, D" uniqKey="Erdman D">D Erdman</name></author><author><name sortKey="Goldsmith, Cs" uniqKey="Goldsmith C">CS Goldsmith</name></author><author><name sortKey="Zaki, Sr" uniqKey="Zaki S">SR 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Lundin</name></noRegion><name sortKey="Adamiak, Beata" sort="Adamiak, Beata" uniqKey="Adamiak B" first="Beata" last="Adamiak">Beata Adamiak</name><name sortKey="Bergstrom, Tomas" sort="Bergstrom, Tomas" uniqKey="Bergstrom T" first="Tomas" last="Bergström">Tomas Bergström</name><name sortKey="Hannoun, Charles" sort="Hannoun, Charles" uniqKey="Hannoun C" first="Charles" last="Hannoun">Charles Hannoun</name><name sortKey="Kann, Nina" sort="Kann, Nina" uniqKey="Kann N" first="Nina" last="Kann">Nina Kann</name><name sortKey="Trybala, Edward" sort="Trybala, Edward" uniqKey="Trybala E" first="Edward" last="Trybala">Edward Trybala</name></country><country name="Suisse"><noRegion><name sortKey="Dijkman, Ronald" sort="Dijkman, Ronald" uniqKey="Dijkman R" first="Ronald" last="Dijkman">Ronald Dijkman</name></noRegion><name sortKey="Dijkman, Ronald" sort="Dijkman, Ronald" uniqKey="Dijkman R" first="Ronald" last="Dijkman">Ronald Dijkman</name><name sortKey="J Nsd Ttir, Hulda R" sort="J Nsd Ttir, 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J Nsd Ttir</name><name sortKey="J Nsd Ttir, Hulda R" sort="J Nsd Ttir, Hulda R" uniqKey="J Nsd Ttir H" first="Hulda R." last="J Nsd Ttir">Hulda R. J Nsd Ttir</name><name sortKey="Kindler, Eveline" sort="Kindler, Eveline" uniqKey="Kindler E" first="Eveline" last="Kindler">Eveline Kindler</name><name sortKey="Kindler, Eveline" sort="Kindler, Eveline" uniqKey="Kindler E" first="Eveline" last="Kindler">Eveline Kindler</name><name sortKey="Thiel, Volker" sort="Thiel, Volker" uniqKey="Thiel V" first="Volker" last="Thiel">Volker Thiel</name><name sortKey="Thiel, Volker" sort="Thiel, Volker" uniqKey="Thiel V" first="Volker" last="Thiel">Volker Thiel</name><name sortKey="Thiel, Volker" sort="Thiel, Volker" uniqKey="Thiel V" first="Volker" last="Thiel">Volker Thiel</name></country><country name="Allemagne"><region name="Rhénanie-du-Nord-Westphalie"><name sortKey="Muth, Doreen" sort="Muth, Doreen" uniqKey="Muth D" first="Doreen" last="Muth">Doreen Muth</name></region><name sortKey="Drosten, Christian" sort="Drosten, Christian" uniqKey="Drosten C" first="Christian" last="Drosten">Christian Drosten</name><name sortKey="Muller, Marcel A" sort="Muller, Marcel A" uniqKey="Muller M" first="Marcel A." last="Müller">Marcel A. Müller</name></country><country name="Pays-Bas"><region name="Gueldre (province)"><name sortKey="Kint, Joeri" sort="Kint, Joeri" uniqKey="Kint J" first="Joeri" last="Kint">Joeri Kint</name></region><name sortKey="Forlenza, Maria" sort="Forlenza, Maria" uniqKey="Forlenza M" first="Maria" last="Forlenza">Maria Forlenza</name><name sortKey="Kint, Joeri" sort="Kint, Joeri" uniqKey="Kint J" first="Joeri" last="Kint">Joeri Kint</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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{{Explor lien
|wiki= Sante
|area= MersV1
|flux= Main
|étape= Exploration
|type= RBID
|clé= PMC:4038610
|texte= Targeting Membrane-Bound Viral RNA Synthesis Reveals Potent Inhibition of Diverse Coronaviruses Including the Middle East Respiratory Syndrome Virus
}}
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HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:24874215" \
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