Rapid identification of coronavirus replicase inhibitors using a selectable replicon RNA
Identifieur interne : 005A79 ( Main/Exploration ); précédent : 005A78; suivant : 005A80Rapid identification of coronavirus replicase inhibitors using a selectable replicon RNA
Auteurs : Tobias Hertzig [Allemagne] ; Elke Scandella [Suisse] ; Barbara Schelle [Allemagne] ; John Ziebuhr [Allemagne] ; Stuart G. Siddell [Royaume-Uni] ; Burkhard Ludewig [Suisse] ; Volker Thiel [Suisse]Source :
- Journal of general virology [ 0022-1317 ] ; 2004.
Descripteurs français
- KwdFr :
- MESH :
- antagonistes et inhibiteurs : RNA replicase.
- génétique : Virus du SRAS.
- pharmacologie : Antiviraux.
- physiologie : ARN viral.
- Pascal (Inist)
English descriptors
- KwdEn :
- Animals, Antiviral Agents (pharmacology), Cell Line, Coronavirus, Identification, Inhibitor, Microbiology, RNA, RNA Replicase (antagonists & inhibitors), RNA, Viral (physiology), RNA-directed RNA polymerase, Replicon, SARS Virus (drug effects), SARS Virus (genetics), Virology, Virus Replication (drug effects).
- MESH :
- chemical , antagonists & inhibitors : RNA Replicase.
- chemical , pharmacology : Antiviral Agents.
- chemical , physiology : RNA, Viral.
- drug effects : SARS Virus, Virus Replication.
- genetics : SARS Virus.
- Animals, Cell Line, Replicon.
Abstract
A previously unknown coronavirus (CoV) is the aetiological agent causing severe acute respiratory syndrome (SARS), for which an effective antiviral treatment is urgently needed. To enable the rapid and biosafe identification of coronavirus replicase inhibitors, we have generated a non-cytopathic, selectable replicon RNA (based on human CoV 229E) that can be stably maintained in eukaryotic cells. Most importantly, the replicon RNA mediates reporter gene expression as a marker for coronavirus replication. We have used a replicon RNA-containing cell line to test the inhibitory effect of several compounds that are currently being assessed for SARS treatment. Amongst those, interferon-α displayed the strongest inhibitory activity. Our results demonstrate that coronavirus replicon cell lines provide a versatile and safe assay for the identification of coronavirus replicase inhibitors. Once this technology is adapted to SARS-CoV replicon RNAs, it will allow high throughput screening for SARS-CoV replicase inhibitors without the need to grow infectious SARS-CoV.
Affiliations:
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first="Tobias" last="Hertzig">Tobias Hertzig</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Institute of Virology and Immunology, University of Würzburg</s1><s2>Würzburg</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Basse-Franconie</region><settlement type="city">Wurtzbourg</settlement></placeName></affiliation></author><author><name sortKey="Scandella, Elke" sort="Scandella, Elke" uniqKey="Scandella E" first="Elke" last="Scandella">Elke Scandella</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Research Department, Cantonal Hospital St Gallen</s1><s2>9007 St Gallen</s2><s3>CHE</s3><sZ>2 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Suisse</country><wicri:noRegion>9007 St Gallen</wicri:noRegion></affiliation></author><author><name sortKey="Schelle, Barbara" sort="Schelle, Barbara" uniqKey="Schelle B" first="Barbara" last="Schelle">Barbara Schelle</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Institute of Virology and Immunology, University of Würzburg</s1><s2>Würzburg</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Basse-Franconie</region><settlement type="city">Wurtzbourg</settlement></placeName></affiliation></author><author><name sortKey="Ziebuhr, John" sort="Ziebuhr, John" uniqKey="Ziebuhr J" first="John" last="Ziebuhr">John Ziebuhr</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Institute of Virology and Immunology, University of Würzburg</s1><s2>Würzburg</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Basse-Franconie</region><settlement type="city">Wurtzbourg</settlement></placeName></affiliation></author><author><name sortKey="Siddell, Stuart G" sort="Siddell, Stuart G" uniqKey="Siddell S" first="Stuart G." last="Siddell">Stuart G. Siddell</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol</s1><s2>Bristol</s2><s3>GBR</s3><sZ>5 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Bristol</wicri:noRegion></affiliation></author><author><name sortKey="Ludewig, Burkhard" sort="Ludewig, Burkhard" uniqKey="Ludewig B" first="Burkhard" last="Ludewig">Burkhard Ludewig</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Research Department, Cantonal Hospital St Gallen</s1><s2>9007 St Gallen</s2><s3>CHE</s3><sZ>2 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Suisse</country><wicri:noRegion>9007 St Gallen</wicri:noRegion></affiliation></author><author><name sortKey="Thiel, Volker" sort="Thiel, Volker" uniqKey="Thiel V" first="Volker" last="Thiel">Volker Thiel</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Research Department, Cantonal Hospital St Gallen</s1><s2>9007 St Gallen</s2><s3>CHE</s3><sZ>2 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Suisse</country><wicri:noRegion>9007 St Gallen</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">Journal of general virology</title><title level="j" type="abbreviated">J. gen. virol.</title><idno type="ISSN">0022-1317</idno><imprint><date when="2004">2004</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Journal of general virology</title><title level="j" type="abbreviated">J. gen. virol.</title><idno type="ISSN">0022-1317</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antiviral Agents (pharmacology)</term><term>Cell Line</term><term>Coronavirus</term><term>Identification</term><term>Inhibitor</term><term>Microbiology</term><term>RNA</term><term>RNA Replicase (antagonists & inhibitors)</term><term>RNA, Viral (physiology)</term><term>RNA-directed RNA polymerase</term><term>Replicon</term><term>SARS Virus (drug effects)</term><term>SARS Virus (genetics)</term><term>Virology</term><term>Virus Replication (drug effects)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>ARN viral (physiologie)</term><term>Animaux</term><term>Antiviraux (pharmacologie)</term><term>Lignée cellulaire</term><term>RNA replicase (antagonistes et inhibiteurs)</term><term>Réplication virale ()</term><term>Réplicon</term><term>Virus du SRAS ()</term><term>Virus du SRAS (génétique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>RNA Replicase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term></keywords><keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>RNA, Viral</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>RNA replicase</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>SARS Virus</term><term>Virus Replication</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>ARN viral</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line</term><term>Replicon</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Animaux</term><term>Coronavirus</term><term>Identification</term><term>Lignée cellulaire</term><term>RNA-directed RNA polymerase</term><term>Inhibiteur</term><term>RNA</term><term>Microbiologie</term><term>Réplication virale</term><term>Réplicon</term><term>Virologie</term><term>Virus du SRAS</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">A previously unknown coronavirus (CoV) is the aetiological agent causing severe acute respiratory syndrome (SARS), for which an effective antiviral treatment is urgently needed. To enable the rapid and biosafe identification of coronavirus replicase inhibitors, we have generated a non-cytopathic, selectable replicon RNA (based on human CoV 229E) that can be stably maintained in eukaryotic cells. Most importantly, the replicon RNA mediates reporter gene expression as a marker for coronavirus replication. We have used a replicon RNA-containing cell line to test the inhibitory effect of several compounds that are currently being assessed for SARS treatment. Amongst those, interferon-α displayed the strongest inhibitory activity. Our results demonstrate that coronavirus replicon cell lines provide a versatile and safe assay for the identification of coronavirus replicase inhibitors. Once this technology is adapted to SARS-CoV replicon RNAs, it will allow high throughput screening for SARS-CoV replicase inhibitors without the need to grow infectious SARS-CoV.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Royaume-Uni</li><li>Suisse</li></country><region><li>Bavière</li><li>District de Basse-Franconie</li></region><settlement><li>Wurtzbourg</li></settlement></list><tree><country name="Allemagne"><region name="Bavière"><name sortKey="Hertzig, Tobias" sort="Hertzig, Tobias" uniqKey="Hertzig T" first="Tobias" last="Hertzig">Tobias Hertzig</name></region><name sortKey="Schelle, Barbara" sort="Schelle, Barbara" uniqKey="Schelle B" first="Barbara" last="Schelle">Barbara Schelle</name><name sortKey="Ziebuhr, John" sort="Ziebuhr, John" uniqKey="Ziebuhr J" first="John" last="Ziebuhr">John Ziebuhr</name></country><country name="Suisse"><noRegion><name sortKey="Scandella, Elke" sort="Scandella, Elke" uniqKey="Scandella E" first="Elke" last="Scandella">Elke Scandella</name></noRegion><name sortKey="Ludewig, Burkhard" sort="Ludewig, Burkhard" uniqKey="Ludewig B" first="Burkhard" last="Ludewig">Burkhard Ludewig</name><name sortKey="Thiel, Volker" sort="Thiel, Volker" uniqKey="Thiel V" first="Volker" last="Thiel">Volker Thiel</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Siddell, Stuart G" sort="Siddell, Stuart G" uniqKey="Siddell S" first="Stuart G." last="Siddell">Stuart G. 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