Targeting membrane-bound viral RNA synthesis reveals potent inhibition of diverse coronaviruses including the middle East respiratory syndrome virus.
Identifieur interne : 001956 ( PubMed/Curation ); précédent : 001955; suivant : 001957Targeting 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 [ 1553-7374 ] ; 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.
DOI: 10.1371/journal.ppat.1004166
PubMed: 24874215
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Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Immunobiology, Kantonal Hospital St.Gallen, St.Gallen, Switzerland; Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern</wicri:regionArea></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:affiliation>Department of Clinical Virology, University of Gothenburg, Göteborg, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Clinical Virology, University of Gothenburg, Göteborg</wicri:regionArea></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:affiliation>Organic Chemistry, Department of Chemical and Biological Engineering, Chalmers University of Technology, Göteborg, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Organic Chemistry, Department of Chemical and Biological Engineering, Chalmers University of Technology, Göteborg</wicri:regionArea></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:affiliation>Department of Clinical Virology, University of Gothenburg, Göteborg, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Clinical Virology, University of Gothenburg, Göteborg</wicri:regionArea></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:affiliation>Department of Clinical Virology, University of Gothenburg, Göteborg, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Clinical Virology, University of Gothenburg, Göteborg</wicri:regionArea></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:affiliation>Institute of Immunobiology, Kantonal Hospital St.Gallen, St.Gallen, Switzerland; Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Immunobiology, Kantonal Hospital St.Gallen, St.Gallen, Switzerland; Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern</wicri:regionArea></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:affiliation>Institute of Immunobiology, Kantonal Hospital St.Gallen, St.Gallen, Switzerland; Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Immunobiology, Kantonal Hospital St.Gallen, St.Gallen, Switzerland; Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern</wicri:regionArea></affiliation></author><author><name sortKey="Muth, Doreen" sort="Muth, Doreen" uniqKey="Muth D" first="Doreen" last="Muth">Doreen Muth</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Virology, University of Bonn Medical Centre, Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Bonn Medical Centre, Bonn</wicri:regionArea></affiliation></author><author><name sortKey="Kint, Joeri" sort="Kint, Joeri" uniqKey="Kint J" first="Joeri" last="Kint">Joeri Kint</name><affiliation wicri:level="1"><nlm:affiliation>Department of Animal Sciences, Cell Biology and Immunology Group, Wageningen Institute of Animal Sciences, Wageningen University, Wageningen, The Netherlands; Merck Animal Health, Bioprocess Technology & Support, Boxmeer, The Netherlands.</nlm:affiliation><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, The Netherlands; Merck Animal Health, Bioprocess Technology & Support, Boxmeer</wicri:regionArea></affiliation></author><author><name sortKey="Forlenza, Maria" sort="Forlenza, Maria" uniqKey="Forlenza M" first="Maria" last="Forlenza">Maria Forlenza</name><affiliation wicri:level="1"><nlm:affiliation>Department of Animal Sciences, Cell Biology and Immunology Group, Wageningen Institute of Animal Sciences, Wageningen University, Wageningen, The Netherlands.</nlm:affiliation><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></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="1"><nlm:affiliation>Institute of Virology, University of Bonn Medical Centre, Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Bonn Medical Centre, Bonn</wicri:regionArea></affiliation></author><author><name sortKey="Drosten, Christian" sort="Drosten, Christian" uniqKey="Drosten C" first="Christian" last="Drosten">Christian Drosten</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Virology, University of Bonn Medical Centre, Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Bonn Medical Centre, Bonn</wicri:regionArea></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:affiliation>Institute of Immunobiology, Kantonal Hospital St.Gallen, St.Gallen, Switzerland; Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern, Switzerland; Vetsuisse Faculty, University of Berne, Berne, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Immunobiology, Kantonal Hospital St.Gallen, St.Gallen, Switzerland; Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern, Switzerland; Vetsuisse Faculty, University of Berne, Berne</wicri:regionArea></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:affiliation>Department of Clinical Virology, University of Gothenburg, Göteborg, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Clinical Virology, University of Gothenburg, Göteborg</wicri:regionArea></affiliation></author></analytic><series><title level="j">PLoS pathogens</title><idno type="eISSN">1553-7374</idno><imprint><date when="2014" type="published">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">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. </div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">24874215</PMID><DateCompleted><Year>2014</Year><Month>11</Month><Day>24</Day></DateCompleted><DateRevised><Year>2018</Year><Month>11</Month><Day>13</Day></DateRevised><Article PubModel="Electronic-eCollection"><Journal><ISSN IssnType="Electronic">1553-7374</ISSN><JournalIssue CitedMedium="Internet"><Volume>10</Volume><Issue>5</Issue><PubDate><Year>2014</Year><Month>May</Month></PubDate></JournalIssue><Title>PLoS pathogens</Title><ISOAbbreviation>PLoS Pathog.</ISOAbbreviation></Journal><ArticleTitle>Targeting membrane-bound viral RNA synthesis reveals potent inhibition of diverse coronaviruses including the middle East respiratory syndrome virus.</ArticleTitle><Pagination><MedlinePgn>e1004166</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1371/journal.ppat.1004166</ELocationID><Abstract><AbstractText>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. </AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Lundin</LastName><ForeName>Anna</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Clinical Virology, University of Gothenburg, Göteborg, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dijkman</LastName><ForeName>Ronald</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Institute of Immunobiology, Kantonal Hospital St.Gallen, St.Gallen, Switzerland; Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bergström</LastName><ForeName>Tomas</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Department of Clinical Virology, University of Gothenburg, Göteborg, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kann</LastName><ForeName>Nina</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Organic Chemistry, Department of Chemical and Biological Engineering, Chalmers University of Technology, Göteborg, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Adamiak</LastName><ForeName>Beata</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Department of Clinical Virology, University of Gothenburg, Göteborg, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hannoun</LastName><ForeName>Charles</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Department of Clinical Virology, University of Gothenburg, Göteborg, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kindler</LastName><ForeName>Eveline</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Institute of Immunobiology, Kantonal Hospital St.Gallen, St.Gallen, Switzerland; Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jónsdóttir</LastName><ForeName>Hulda R</ForeName><Initials>HR</Initials><AffiliationInfo><Affiliation>Institute of Immunobiology, Kantonal Hospital St.Gallen, St.Gallen, Switzerland; Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Muth</LastName><ForeName>Doreen</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Institute of Virology, University of Bonn Medical Centre, Bonn, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kint</LastName><ForeName>Joeri</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Animal Sciences, Cell Biology and Immunology Group, Wageningen Institute of Animal Sciences, Wageningen University, Wageningen, The Netherlands; Merck Animal Health, Bioprocess Technology & Support, Boxmeer, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Forlenza</LastName><ForeName>Maria</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Animal Sciences, Cell Biology and Immunology Group, Wageningen Institute of Animal Sciences, Wageningen University, Wageningen, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Müller</LastName><ForeName>Marcel A</ForeName><Initials>MA</Initials><AffiliationInfo><Affiliation>Institute of Virology, University of Bonn Medical Centre, Bonn, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Drosten</LastName><ForeName>Christian</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Institute of Virology, University of Bonn Medical Centre, Bonn, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Thiel</LastName><ForeName>Volker</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Institute of Immunobiology, Kantonal Hospital St.Gallen, St.Gallen, Switzerland; Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern, Switzerland; Vetsuisse Faculty, University of Berne, Berne, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Trybala</LastName><ForeName>Edward</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Department of Clinical Virology, University of Gothenburg, Göteborg, Sweden.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2014</Year><Month>05</Month><Day>29</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>PLoS Pathog</MedlineTA><NlmUniqueID>101238921</NlmUniqueID><ISSNLinking>1553-7366</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000998">Antiviral Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D012367">RNA, Viral</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000998" MajorTopicYN="N">Antiviral Agents</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002460" MajorTopicYN="N">Cell Line</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002462" MajorTopicYN="N">Cell Membrane</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017934" MajorTopicYN="Y">Coronavirus</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018352" MajorTopicYN="N">Coronavirus Infections</DescriptorName><QualifierName UI="Q000517" MajorTopicYN="N">prevention & control</QualifierName><QualifierName UI="Q000821" MajorTopicYN="Y">virology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012367" MajorTopicYN="N">RNA, Viral</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012136" MajorTopicYN="Y">Respiratory Syncytial Viruses</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D053586" MajorTopicYN="N">Virus Internalization</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014779" MajorTopicYN="N">Virus Replication</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2013</Year><Month>10</Month><Day>10</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2014</Year><Month>04</Month><Day>21</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2014</Year><Month>5</Month><Day>31</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2014</Year><Month>5</Month><Day>31</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2014</Year><Month>12</Month><Day>15</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">24874215</ArticleId><ArticleId 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