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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Cinanserin Is an Inhibitor of the 3C-Like Proteinase of Severe Acute Respiratory Syndrome Coronavirus and Strongly Reduces Virus Replication In Vitro<xref ref-type="fn" rid="fn1">†</xref> </title><author><name sortKey="Chen, Lili" sort="Chen, Lili" uniqKey="Chen L" first="Lili" last="Chen">Lili Chen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Gui, Chunshan" sort="Gui, Chunshan" uniqKey="Gui C" first="Chunshan" last="Gui">Chunshan Gui</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Luo, Xiaomin" sort="Luo, Xiaomin" uniqKey="Luo X" first="Xiaomin" last="Luo">Xiaomin Luo</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Yang, Qingang" sort="Yang, Qingang" uniqKey="Yang Q" first="Qingang" last="Yang">Qingang Yang</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Gunther, Stephan" sort="Gunther, Stephan" uniqKey="Gunther S" first="Stephan" last="Günther">Stephan Günther</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Scandella, Elke" sort="Scandella, Elke" uniqKey="Scandella E" first="Elke" last="Scandella">Elke Scandella</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Drosten, Christian" sort="Drosten, Christian" uniqKey="Drosten C" first="Christian" last="Drosten">Christian Drosten</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Bai, Donglu" sort="Bai, Donglu" uniqKey="Bai D" first="Donglu" last="Bai">Donglu Bai</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="He, Xichang" sort="He, Xichang" uniqKey="He X" first="Xichang" last="He">Xichang He</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Ludewig, Burkhard" sort="Ludewig, Burkhard" uniqKey="Ludewig B" first="Burkhard" last="Ludewig">Burkhard Ludewig</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Chen, Jing" sort="Chen, Jing" uniqKey="Chen J" first="Jing" last="Chen">Jing Chen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Luo, Haibin" sort="Luo, Haibin" uniqKey="Luo H" first="Haibin" last="Luo">Haibin Luo</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Yang, Yiming" sort="Yang, Yiming" uniqKey="Yang Y" first="Yiming" last="Yang">Yiming Yang</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Yang, Yifu" sort="Yang, Yifu" uniqKey="Yang Y" first="Yifu" last="Yang">Yifu Yang</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Zou, Jianping" sort="Zou, Jianping" uniqKey="Zou J" first="Jianping" last="Zou">Jianping Zou</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Thiel, Volker" sort="Thiel, Volker" uniqKey="Thiel V" first="Volker" last="Thiel">Volker Thiel</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Chen, Kaixian" sort="Chen, Kaixian" uniqKey="Chen K" first="Kaixian" last="Chen">Kaixian Chen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Shen, Jianhua" sort="Shen, Jianhua" uniqKey="Shen J" first="Jianhua" last="Shen">Jianhua Shen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Shen, Xu" sort="Shen, Xu" uniqKey="Shen X" first="Xu" last="Shen">Xu Shen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Jiang, Hualiang" sort="Jiang, Hualiang" uniqKey="Jiang H" first="Hualiang" last="Jiang">Hualiang Jiang</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">15890949</idno><idno type="pmc">1112131</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1112131</idno><idno type="RBID">PMC:1112131</idno><idno type="doi">10.1128/JVI.79.11.7095-7103.2005</idno><date when="2005">2005</date><idno type="wicri:Area/Pmc/Corpus">000694</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000694</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Cinanserin Is an Inhibitor of the 3C-Like Proteinase of Severe Acute Respiratory Syndrome Coronavirus and Strongly Reduces Virus Replication In Vitro<xref ref-type="fn" rid="fn1">†</xref> </title><author><name sortKey="Chen, Lili" sort="Chen, Lili" uniqKey="Chen L" first="Lili" last="Chen">Lili Chen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Gui, Chunshan" sort="Gui, Chunshan" uniqKey="Gui C" first="Chunshan" last="Gui">Chunshan Gui</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Luo, Xiaomin" sort="Luo, Xiaomin" uniqKey="Luo X" first="Xiaomin" last="Luo">Xiaomin Luo</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Yang, Qingang" sort="Yang, Qingang" uniqKey="Yang Q" first="Qingang" last="Yang">Qingang Yang</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Gunther, Stephan" sort="Gunther, Stephan" uniqKey="Gunther S" first="Stephan" last="Günther">Stephan Günther</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Scandella, Elke" sort="Scandella, Elke" uniqKey="Scandella E" first="Elke" last="Scandella">Elke Scandella</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Drosten, Christian" sort="Drosten, Christian" uniqKey="Drosten C" first="Christian" last="Drosten">Christian Drosten</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Bai, Donglu" sort="Bai, Donglu" uniqKey="Bai D" first="Donglu" last="Bai">Donglu Bai</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="He, Xichang" sort="He, Xichang" uniqKey="He X" first="Xichang" last="He">Xichang He</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Ludewig, Burkhard" sort="Ludewig, Burkhard" uniqKey="Ludewig B" first="Burkhard" last="Ludewig">Burkhard Ludewig</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Chen, Jing" sort="Chen, Jing" uniqKey="Chen J" first="Jing" last="Chen">Jing Chen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Luo, Haibin" sort="Luo, Haibin" uniqKey="Luo H" first="Haibin" last="Luo">Haibin Luo</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Yang, Yiming" sort="Yang, Yiming" uniqKey="Yang Y" first="Yiming" last="Yang">Yiming Yang</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Yang, Yifu" sort="Yang, Yifu" uniqKey="Yang Y" first="Yifu" last="Yang">Yifu Yang</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Zou, Jianping" sort="Zou, Jianping" uniqKey="Zou J" first="Jianping" last="Zou">Jianping Zou</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Thiel, Volker" sort="Thiel, Volker" uniqKey="Thiel V" first="Volker" last="Thiel">Volker Thiel</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Chen, Kaixian" sort="Chen, Kaixian" uniqKey="Chen K" first="Kaixian" last="Chen">Kaixian Chen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Shen, Jianhua" sort="Shen, Jianhua" uniqKey="Shen J" first="Jianhua" last="Shen">Jianhua Shen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Shen, Xu" sort="Shen, Xu" uniqKey="Shen X" first="Xu" last="Shen">Xu Shen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Jiang, Hualiang" sort="Jiang, Hualiang" uniqKey="Jiang H" first="Hualiang" last="Jiang">Hualiang Jiang</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Virology</title><idno type="ISSN">0022-538X</idno><idno type="eISSN">1098-5514</idno><imprint><date when="2005">2005</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The 3C-like proteinase (3CL<sup>pro</sup>) of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is one of the most promising targets for anti-SARS-CoV drugs due to its crucial role in the viral life cycle. In this study, a database containing structural information of more than 8,000 existing drugs was virtually screened by a docking approach to identify potential binding molecules of SARS-CoV 3CL<sup>pro</sup>. As a target for screening, both a homology model and the crystallographic structure of the binding pocket of the enzyme were used. Cinanserin (SQ 10,643), a well-characterized serotonin antagonist that has undergone preliminary clinical testing in humans in the 1960s, showed a high score in the screening and was chosen for further experimental evaluation. Binding of both cinanserin and its hydrochloride to bacterially expressed 3CL<sup>pro</sup> of SARS-CoV and the related human coronavirus 229E (HCoV-229E) was demonstrated by surface plasmon resonance technology. The catalytic activity of both enzymes was inhibited with 50% inhibitory concentration (IC<sub>50</sub>) values of 5 μM, as tested with a fluorogenic substrate. The antiviral activity of cinanserin was further evaluated in tissue culture assays, namely, a replicon system based on HCoV-229E and quantitative test assays with infectious SARS-CoV and HCoV-229E. All assays revealed a strong inhibition of coronavirus replication at nontoxic drug concentrations. The level of virus RNA and infectious particles was reduced by up to 4 log units, with IC<sub>50</sub> values ranging from 19 to 34 μM. These findings demonstrate that the old drug cinanserin is an inhibitor of SARS-CoV replication, acting most likely via inhibition of the 3CL proteinase.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Virol</journal-id><journal-id journal-id-type="publisher-id">jvi</journal-id><journal-title>Journal of Virology</journal-title><issn pub-type="ppub">0022-538X</issn><issn pub-type="epub">1098-5514</issn><publisher><publisher-name>American Society for Microbiology</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">15890949</article-id><article-id pub-id-type="pmc">1112131</article-id><article-id pub-id-type="publisher-id">2484-04</article-id><article-id pub-id-type="doi">10.1128/JVI.79.11.7095-7103.2005</article-id><article-categories><subj-group subj-group-type="heading"><subject>Vaccines and Antiviral Agents</subject></subj-group></article-categories><title-group><article-title>Cinanserin Is an Inhibitor of the 3C-Like Proteinase of Severe Acute Respiratory Syndrome Coronavirus and Strongly Reduces Virus Replication In Vitro<xref ref-type="fn" rid="fn1">†</xref> </article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Lili</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="fn" rid="fn2">‡</xref></contrib><contrib contrib-type="author"><name><surname>Gui</surname><given-names>Chunshan</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="fn" rid="fn2">‡</xref></contrib><contrib contrib-type="author"><name><surname>Luo</surname><given-names>Xiaomin</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="fn" rid="fn2">‡</xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Qingang</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="fn" rid="fn2">‡</xref></contrib><contrib contrib-type="author"><name><surname>Günther</surname><given-names>Stephan</given-names></name><xref ref-type="aff" rid="aff1">2</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><contrib contrib-type="author"><name><surname>Scandella</surname><given-names>Elke</given-names></name><xref ref-type="aff" rid="aff1">3</xref></contrib><contrib contrib-type="author"><name><surname>Drosten</surname><given-names>Christian</given-names></name><xref ref-type="aff" rid="aff1">2</xref></contrib><contrib contrib-type="author"><name><surname>Bai</surname><given-names>Donglu</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>He</surname><given-names>Xichang</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Ludewig</surname><given-names>Burkhard</given-names></name><xref ref-type="aff" rid="aff1">3</xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Jing</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Luo</surname><given-names>Haibin</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Yiming</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Yifu</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Zou</surname><given-names>Jianping</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Thiel</surname><given-names>Volker</given-names></name><xref ref-type="aff" rid="aff1">3</xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Kaixian</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Shen</surname><given-names>Jianhua</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Shen</surname><given-names>Xu</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><contrib contrib-type="author"><name><surname>Jiang</surname><given-names>Hualiang</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff1">4</xref></contrib></contrib-group><aff id="aff1">Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China,<label>1</label> Department of Virology, Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Str. 74, 20359 Hamburg, Germany,<label>2</label> Research Department, Kantonal Hospital St. Gallen, CH-9007 St. Gallen, Switzerland,<label>3</label> School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China<label>4</label></aff><author-notes><fn id="cor1"><label>*</label><p>Corresponding author. Mailing address for Stephan Günther: Department of Virology, Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Str. 74, 20359 Hamburg, Germany. Phone: 49 40 42818 421. Fax: 49 40 42818 378. E-mail: <email>guenther@bni.uni-hamburg.de</email>. Mailing address for Xu Shen: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China. Phone: 86 21 50806918. Fax: 86 21 50807088. E-mail: <email>xshen@mail.shcnc.ac.cn</email>.</p></fn><fn id="fn2"><label>‡</label><p>These authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="ppub"><month>6</month><year>2005</year></pub-date><volume>79</volume><issue>11</issue><fpage>7095</fpage><lpage>7103</lpage><history><date date-type="received"><day>22</day><month>10</month><year>2004</year></date><date date-type="accepted"><day>14</day><month>1</month><year>2005</year></date></history><copyright-statement>Copyright © 2005, American Society for Microbiology</copyright-statement><copyright-year>2005</copyright-year><abstract><p>The 3C-like proteinase (3CL<sup>pro</sup>) of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is one of the most promising targets for anti-SARS-CoV drugs due to its crucial role in the viral life cycle. In this study, a database containing structural information of more than 8,000 existing drugs was virtually screened by a docking approach to identify potential binding molecules of SARS-CoV 3CL<sup>pro</sup>. As a target for screening, both a homology model and the crystallographic structure of the binding pocket of the enzyme were used. Cinanserin (SQ 10,643), a well-characterized serotonin antagonist that has undergone preliminary clinical testing in humans in the 1960s, showed a high score in the screening and was chosen for further experimental evaluation. Binding of both cinanserin and its hydrochloride to bacterially expressed 3CL<sup>pro</sup> of SARS-CoV and the related human coronavirus 229E (HCoV-229E) was demonstrated by surface plasmon resonance technology. The catalytic activity of both enzymes was inhibited with 50% inhibitory concentration (IC<sub>50</sub>) values of 5 μM, as tested with a fluorogenic substrate. The antiviral activity of cinanserin was further evaluated in tissue culture assays, namely, a replicon system based on HCoV-229E and quantitative test assays with infectious SARS-CoV and HCoV-229E. All assays revealed a strong inhibition of coronavirus replication at nontoxic drug concentrations. The level of virus RNA and infectious particles was reduced by up to 4 log units, with IC<sub>50</sub> values ranging from 19 to 34 μM. These findings demonstrate that the old drug cinanserin is an inhibitor of SARS-CoV replication, acting most likely via inhibition of the 3CL proteinase.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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