Cinanserin is an inhibitor of the 3C-like proteinase of severe acute respiratory syndrome coronavirus and strongly reduces virus replication in vitro.
Identifieur interne : 002744 ( PubMed/Curation ); précédent : 002743; suivant : 002745Cinanserin 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.
Descripteurs français
- KwdFr :
- ADN viral (génétique), Animaux, Antiviraux (), Antiviraux (pharmacologie), Cellules Vero, Cinansérine (), Cinansérine (pharmacologie), Cricetinae, Cysteine endopeptidases, Endopeptidases (), Endopeptidases (génétique), Humains, Inhibiteurs de protéases (), Inhibiteurs de protéases (pharmacologie), Interface utilisateur, Lignée cellulaire, Modèles moléculaires, Protéines recombinantes (antagonistes et inhibiteurs), Protéines recombinantes (génétique), Protéines virales (), Protéines virales (antagonistes et inhibiteurs), Protéines virales (génétique), RNA replicase (antagonistes et inhibiteurs), Réplication virale (), Séquence nucléotidique, Techniques in vitro, Virus du SRAS (), Virus du SRAS (enzymologie), Virus du SRAS (génétique), Virus du SRAS (physiologie), Évaluation préclinique de médicament ().
- MESH :
- antagonistes et inhibiteurs : Protéines recombinantes, Protéines virales, RNA replicase.
- enzymologie : Virus du SRAS.
- génétique : ADN viral, Endopeptidases, Protéines recombinantes, Protéines virales, Virus du SRAS.
- pharmacologie : Antiviraux, Cinansérine, Inhibiteurs de protéases.
- physiologie : Virus du SRAS.
- Animaux, Antiviraux, Cellules Vero, Cinansérine, Cricetinae, Cysteine endopeptidases, Endopeptidases, Humains, Inhibiteurs de protéases, Interface utilisateur, Lignée cellulaire, Modèles moléculaires, Protéines virales, Réplication virale, Séquence nucléotidique, Techniques in vitro, Virus du SRAS, Évaluation préclinique de médicament.
English descriptors
- KwdEn :
- Animals, Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Base Sequence, Cell Line, Chlorocebus aethiops, Cinanserin (chemistry), Cinanserin (pharmacology), Cricetinae, Cysteine Endopeptidases, DNA, Viral (genetics), Drug Evaluation, Preclinical (methods), Endopeptidases (chemistry), Endopeptidases (genetics), Humans, In Vitro Techniques, Models, Molecular, Protease Inhibitors (chemistry), Protease Inhibitors (pharmacology), RNA Replicase (antagonists & inhibitors), Recombinant Proteins (antagonists & inhibitors), Recombinant Proteins (genetics), SARS Virus (drug effects), SARS Virus (enzymology), SARS Virus (genetics), SARS Virus (physiology), User-Computer Interface, Vero Cells, Viral Proteins (antagonists & inhibitors), Viral Proteins (chemistry), Viral Proteins (genetics), Virus Replication (drug effects).
- MESH :
- chemical , antagonists & inhibitors : RNA Replicase, Recombinant Proteins, Viral Proteins.
- chemical , chemistry : Antiviral Agents, Cinanserin, Endopeptidases, Protease Inhibitors, Viral Proteins.
- chemical , genetics : DNA, Viral, Endopeptidases, Recombinant Proteins, Viral Proteins.
- chemical , pharmacology : Antiviral Agents, Cinanserin, Protease Inhibitors.
- drug effects : SARS Virus, Virus Replication.
- enzymology : SARS Virus.
- genetics : SARS Virus.
- methods : Drug Evaluation, Preclinical.
- physiology : SARS Virus.
- Animals, Base Sequence, Cell Line, Chlorocebus aethiops, Cricetinae, Cysteine Endopeptidases, Humans, In Vitro Techniques, Models, Molecular, User-Computer Interface, Vero Cells.
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 microM, 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 microM. These findings demonstrate that the old drug cinanserin is an inhibitor of SARS-CoV replication, acting most likely via inhibition of the 3CL proteinase.
DOI: 10.1128/JVI.79.11.7095-7103.2005
PubMed: 15890949
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Lili Chen<affiliation><nlm:affiliation>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.</nlm:affiliation>
<wicri:noCountry code="subField">Chinese Academy of Sciences</wicri:noCountry>
</affiliation>
Le document en format XML
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<term>Base Sequence</term>
<term>Cell Line</term>
<term>Chlorocebus aethiops</term>
<term>Cinanserin (chemistry)</term>
<term>Cinanserin (pharmacology)</term>
<term>Cricetinae</term>
<term>Cysteine Endopeptidases</term>
<term>DNA, Viral (genetics)</term>
<term>Drug Evaluation, Preclinical (methods)</term>
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<term>Endopeptidases (genetics)</term>
<term>Humans</term>
<term>In Vitro Techniques</term>
<term>Models, Molecular</term>
<term>Protease Inhibitors (chemistry)</term>
<term>Protease Inhibitors (pharmacology)</term>
<term>RNA Replicase (antagonists & inhibitors)</term>
<term>Recombinant Proteins (antagonists & inhibitors)</term>
<term>Recombinant Proteins (genetics)</term>
<term>SARS Virus (drug effects)</term>
<term>SARS Virus (enzymology)</term>
<term>SARS Virus (genetics)</term>
<term>SARS Virus (physiology)</term>
<term>User-Computer Interface</term>
<term>Vero Cells</term>
<term>Viral Proteins (antagonists & inhibitors)</term>
<term>Viral Proteins (chemistry)</term>
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<keywords scheme="KwdFr" xml:lang="fr"><term>ADN viral (génétique)</term>
<term>Animaux</term>
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<term>Antiviraux (pharmacologie)</term>
<term>Cellules Vero</term>
<term>Cinansérine ()</term>
<term>Cinansérine (pharmacologie)</term>
<term>Cricetinae</term>
<term>Cysteine endopeptidases</term>
<term>Endopeptidases ()</term>
<term>Endopeptidases (génétique)</term>
<term>Humains</term>
<term>Inhibiteurs de protéases ()</term>
<term>Inhibiteurs de protéases (pharmacologie)</term>
<term>Interface utilisateur</term>
<term>Lignée cellulaire</term>
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<term>Protéines recombinantes (génétique)</term>
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<term>Protéines virales (antagonistes et inhibiteurs)</term>
<term>Protéines virales (génétique)</term>
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<term>Réplication virale ()</term>
<term>Séquence nucléotidique</term>
<term>Techniques in vitro</term>
<term>Virus du SRAS ()</term>
<term>Virus du SRAS (enzymologie)</term>
<term>Virus du SRAS (génétique)</term>
<term>Virus du SRAS (physiologie)</term>
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<term>Viral Proteins</term>
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<term>Endopeptidases</term>
<term>Protease Inhibitors</term>
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<term>Protéines virales</term>
<term>Virus du SRAS</term>
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<term>Inhibiteurs de protéases</term>
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<keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>SARS Virus</term>
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<term>Base Sequence</term>
<term>Cell Line</term>
<term>Chlorocebus aethiops</term>
<term>Cricetinae</term>
<term>Cysteine Endopeptidases</term>
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<term>In Vitro Techniques</term>
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<term>User-Computer Interface</term>
<term>Vero Cells</term>
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<term>Antiviraux</term>
<term>Cellules Vero</term>
<term>Cinansérine</term>
<term>Cricetinae</term>
<term>Cysteine endopeptidases</term>
<term>Endopeptidases</term>
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<term>Inhibiteurs de protéases</term>
<term>Interface utilisateur</term>
<term>Lignée cellulaire</term>
<term>Modèles moléculaires</term>
<term>Protéines virales</term>
<term>Réplication virale</term>
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<front><div type="abstract" xml:lang="en">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 microM, 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 microM. These findings demonstrate that the old drug cinanserin is an inhibitor of SARS-CoV replication, acting most likely via inhibition of the 3CL proteinase.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">15890949</PMID>
<DateCompleted><Year>2005</Year>
<Month>06</Month>
<Day>14</Day>
</DateCompleted>
<DateRevised><Year>2020</Year>
<Month>03</Month>
<Day>25</Day>
</DateRevised>
<Article PubModel="Print"><Journal><ISSN IssnType="Print">0022-538X</ISSN>
<JournalIssue CitedMedium="Print"><Volume>79</Volume>
<Issue>11</Issue>
<PubDate><Year>2005</Year>
<Month>Jun</Month>
</PubDate>
</JournalIssue>
<Title>Journal of virology</Title>
<ISOAbbreviation>J. Virol.</ISOAbbreviation>
</Journal>
<ArticleTitle>Cinanserin is an inhibitor of the 3C-like proteinase of severe acute respiratory syndrome coronavirus and strongly reduces virus replication in vitro.</ArticleTitle>
<Pagination><MedlinePgn>7095-103</MedlinePgn>
</Pagination>
<Abstract><AbstractText>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 microM, 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 microM. These findings demonstrate that the old drug cinanserin is an inhibitor of SARS-CoV replication, acting most likely via inhibition of the 3CL proteinase.</AbstractText>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Chen</LastName>
<ForeName>Lili</ForeName>
<Initials>L</Initials>
<AffiliationInfo><Affiliation>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.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Gui</LastName>
<ForeName>Chunshan</ForeName>
<Initials>C</Initials>
</Author>
<Author ValidYN="Y"><LastName>Luo</LastName>
<ForeName>Xiaomin</ForeName>
<Initials>X</Initials>
</Author>
<Author ValidYN="Y"><LastName>Yang</LastName>
<ForeName>Qingang</ForeName>
<Initials>Q</Initials>
</Author>
<Author ValidYN="Y"><LastName>Günther</LastName>
<ForeName>Stephan</ForeName>
<Initials>S</Initials>
</Author>
<Author ValidYN="Y"><LastName>Scandella</LastName>
<ForeName>Elke</ForeName>
<Initials>E</Initials>
</Author>
<Author ValidYN="Y"><LastName>Drosten</LastName>
<ForeName>Christian</ForeName>
<Initials>C</Initials>
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<Author ValidYN="Y"><LastName>Bai</LastName>
<ForeName>Donglu</ForeName>
<Initials>D</Initials>
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<Author ValidYN="Y"><LastName>He</LastName>
<ForeName>Xichang</ForeName>
<Initials>X</Initials>
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