Cinanserin Is an Inhibitor of the 3C-Like Proteinase of Severe Acute Respiratory Syndrome Coronavirus and Strongly Reduces Virus Replication In Vitro†
Identifieur interne : 000694 ( Pmc/Curation ); précédent : 000693; suivant : 000695Cinanserin Is an Inhibitor of the 3C-Like Proteinase of Severe Acute Respiratory Syndrome Coronavirus and Strongly Reduces Virus Replication In Vitro†
Auteurs : Lili Chen ; Chunshan Gui ; Xiaomin Luo ; Qingang Yang ; Stephan Günther ; Elke Scandella ; Christian Drosten ; Donglu Bai ; Xichang He ; Burkhard Ludewig ; Jing Chen ; Haibin Luo ; Yiming Yang ; Yifu Yang ; Jianping Zou ; Volker Thiel ; Kaixian Chen ; Jianhua Shen ; Xu Shen ; Hualiang JiangSource :
- Journal of Virology [ 0022-538X ] ; 2005.
Abstract
The 3C-like proteinase (3CLpro) 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 3CLpro. 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 3CLpro 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 (IC50) 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 IC50 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.
Url:
DOI: 10.1128/JVI.79.11.7095-7103.2005
PubMed: 15890949
PubMed Central: 1112131
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<series><title level="j">Journal of Virology</title>
<idno type="ISSN">0022-538X</idno>
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<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>
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