Cinanserin is an inhibitor of the 3C-like proteinase of severe acute respiratory syndrome coronavirus and strongly reduces virus replication in vitro
Identifieur interne : 000316 ( PascalFrancis/Curation ); précédent : 000315; suivant : 000317Cinanserin is an inhibitor of the 3C-like proteinase of severe acute respiratory syndrome coronavirus and strongly reduces virus replication in vitro
Auteurs : LILI CHEN [République populaire de Chine] ; CHUNSHAN GUI [République populaire de Chine] ; XIAOMIN LUO [République populaire de Chine] ; QINGANG YANG [République populaire de Chine] ; Stephan Günther [Allemagne] ; Elke Scandella [Suisse] ; Christian Drosten [Allemagne] ; DONGLU BAI [République populaire de Chine] ; XICHANG HE [République populaire de Chine] ; Burkhard Ludewig [Suisse] ; JING CHEN [République populaire de Chine] ; HAIBIN LUO [République populaire de Chine] ; YIMING YANG [République populaire de Chine] ; YIFU YANG [République populaire de Chine] ; JIANPING ZOU [République populaire de Chine] ; Volker Thiel [Suisse] ; KAIXIAN CHEN [République populaire de Chine] ; JIANHUA SHEN [République populaire de Chine] ; XU SHEN [République populaire de Chine] ; HUALIANG JIANG [République populaire de Chine]Source :
- Journal of virology [ 0022-538X ] ; 2005.
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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.
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first="Christian" last="Drosten">Christian Drosten</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Virology, Bemhard Nocht Institute for Tropical Medicine, Bemhard-Nocht-Str. 74</s1><s2>20359 Hamburg</s2><s3>DEU</s3><sZ>5 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation></author><author><name sortKey="Donglu Bai" sort="Donglu Bai" uniqKey="Donglu Bai" last="Donglu Bai">DONGLU BAI</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></affiliation></author><author><name sortKey="Xichang He" sort="Xichang He" uniqKey="Xichang He" last="Xichang He">XICHANG HE</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></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="03"><s1>Research Department, Kantonal Hospital St. Gallon</s1><s2>9007 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Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></affiliation></author><author><name sortKey="Yiming Yang" sort="Yiming Yang" uniqKey="Yiming Yang" last="Yiming Yang">YIMING YANG</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 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sort="Jianping Zou" uniqKey="Jianping Zou" last="Jianping Zou">JIANPING ZOU</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></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="03"><s1>Research Department, Kantonal Hospital St. Gallon</s1><s2>9007 St. Gallen</s2><s3>CHE</s3><sZ>6 aut.</sZ><sZ>10 aut.</sZ><sZ>16 aut.</sZ></inist:fA14><country>Suisse</country></affiliation></author><author><name sortKey="Kaixian Chen" sort="Kaixian Chen" uniqKey="Kaixian Chen" last="Kaixian Chen">KAIXIAN CHEN</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></affiliation></author><author><name sortKey="Jianhua Shen" sort="Jianhua Shen" uniqKey="Jianhua Shen" last="Jianhua Shen">JIANHUA SHEN</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></affiliation></author><author><name sortKey="Xu Shen" sort="Xu Shen" uniqKey="Xu Shen" last="Xu Shen">XU SHEN</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></affiliation></author><author><name sortKey="Hualiang Jiang" sort="Hualiang Jiang" uniqKey="Hualiang Jiang" last="Hualiang Jiang">HUALIANG JIANG</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>School of Pharmacy, East China University of Science and Technology</s1><s2>Shanghai 200237</s2><s3>CHN</s3><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">05-0248689</idno><date when="2005">2005</date><idno type="stanalyst">PASCAL 05-0248689 INIST</idno><idno type="RBID">Pascal:05-0248689</idno><idno type="wicri:Area/PascalFrancis/Corpus">000674</idno><idno type="wicri:Area/PascalFrancis/Curation">000316</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Cinanserin is an inhibitor of the 3C-like proteinase of severe acute respiratory syndrome coronavirus and strongly reduces virus replication in vitro</title><author><name sortKey="Lili Chen" sort="Lili Chen" uniqKey="Lili Chen" last="Lili Chen">LILI CHEN</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></affiliation></author><author><name sortKey="Chunshan Gui" sort="Chunshan Gui" uniqKey="Chunshan Gui" last="Chunshan Gui">CHUNSHAN GUI</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 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YANG</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></affiliation></author><author><name sortKey="Gunther, Stephan" sort="Gunther, Stephan" uniqKey="Gunther S" first="Stephan" last="Günther">Stephan Günther</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Virology, Bemhard Nocht Institute for Tropical Medicine, Bemhard-Nocht-Str. 74</s1><s2>20359 Hamburg</s2><s3>DEU</s3><sZ>5 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Allemagne</country></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="03"><s1>Research Department, Kantonal Hospital St. Gallon</s1><s2>9007 St. Gallen</s2><s3>CHE</s3><sZ>6 aut.</sZ><sZ>10 aut.</sZ><sZ>16 aut.</sZ></inist:fA14><country>Suisse</country></affiliation></author><author><name sortKey="Drosten, Christian" sort="Drosten, Christian" uniqKey="Drosten C" first="Christian" last="Drosten">Christian Drosten</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Virology, Bemhard Nocht Institute for Tropical Medicine, Bemhard-Nocht-Str. 74</s1><s2>20359 Hamburg</s2><s3>DEU</s3><sZ>5 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation></author><author><name sortKey="Donglu Bai" sort="Donglu Bai" uniqKey="Donglu Bai" last="Donglu Bai">DONGLU BAI</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></affiliation></author><author><name sortKey="Xichang He" sort="Xichang He" uniqKey="Xichang He" last="Xichang He">XICHANG HE</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></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="03"><s1>Research Department, Kantonal Hospital St. Gallon</s1><s2>9007 St. Gallen</s2><s3>CHE</s3><sZ>6 aut.</sZ><sZ>10 aut.</sZ><sZ>16 aut.</sZ></inist:fA14><country>Suisse</country></affiliation></author><author><name sortKey="Jing Chen" sort="Jing Chen" uniqKey="Jing Chen" last="Jing Chen">JING CHEN</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></affiliation></author><author><name sortKey="Haibin Luo" sort="Haibin Luo" uniqKey="Haibin Luo" last="Haibin Luo">HAIBIN LUO</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></affiliation></author><author><name sortKey="Yiming Yang" sort="Yiming Yang" uniqKey="Yiming Yang" last="Yiming Yang">YIMING YANG</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></affiliation></author><author><name sortKey="Yifu Yang" sort="Yifu Yang" uniqKey="Yifu Yang" last="Yifu Yang">YIFU YANG</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></affiliation></author><author><name sortKey="Jianping Zou" sort="Jianping Zou" uniqKey="Jianping Zou" last="Jianping Zou">JIANPING ZOU</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></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="03"><s1>Research Department, Kantonal Hospital St. Gallon</s1><s2>9007 St. Gallen</s2><s3>CHE</s3><sZ>6 aut.</sZ><sZ>10 aut.</sZ><sZ>16 aut.</sZ></inist:fA14><country>Suisse</country></affiliation></author><author><name sortKey="Kaixian Chen" sort="Kaixian Chen" uniqKey="Kaixian Chen" last="Kaixian Chen">KAIXIAN CHEN</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></affiliation></author><author><name sortKey="Jianhua Shen" sort="Jianhua Shen" uniqKey="Jianhua Shen" last="Jianhua Shen">JIANHUA SHEN</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></affiliation></author><author><name sortKey="Xu Shen" sort="Xu Shen" uniqKey="Xu Shen" last="Xu Shen">XU SHEN</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></affiliation></author><author><name sortKey="Hualiang Jiang" sort="Hualiang Jiang" uniqKey="Hualiang Jiang" last="Hualiang Jiang">HUALIANG JIANG</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>School of Pharmacy, East China University of Science and Technology</s1><s2>Shanghai 200237</s2><s3>CHN</s3><sZ>20 aut.</sZ></inist:fA14><country>République populaire de Chine</country></affiliation></author></analytic><series><title level="j" type="main">Journal of virology</title><title level="j" type="abbreviated">J. virol.</title><idno type="ISSN">0022-538X</idno><imprint><date when="2005">2005</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Journal of virology</title><title level="j" type="abbreviated">J. virol.</title><idno type="ISSN">0022-538X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Cinanserin</term><term>Coronavirus</term><term>In vitro replication</term><term>Microbiology</term><term>Peptidases</term><term>Severe acute respiratory syndrome</term><term>Virology</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Coronavirus</term><term>Peptidases</term><term>Replication in vitro</term><term>Microbiologie</term><term>Virologie</term><term>Cinansérine</term><term>Syndrome respiratoire aigu sévère</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0022-538X</s0></fA01><fA03 i2="1"><s0>J. virol.</s0></fA03><fA05><s2>79</s2></fA05><fA06><s2>11</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>Cinanserin is an inhibitor of the 3C-like proteinase of severe acute respiratory syndrome coronavirus and strongly reduces virus replication in vitro</s1></fA08><fA11 i1="01" i2="1"><s1>LILI CHEN</s1></fA11><fA11 i1="02" i2="1"><s1>CHUNSHAN GUI</s1></fA11><fA11 i1="03" i2="1"><s1>XIAOMIN LUO</s1></fA11><fA11 i1="04" i2="1"><s1>QINGANG YANG</s1></fA11><fA11 i1="05" i2="1"><s1>GÜNTHER (Stephan)</s1></fA11><fA11 i1="06" i2="1"><s1>SCANDELLA (Elke)</s1></fA11><fA11 i1="07" i2="1"><s1>DROSTEN (Christian)</s1></fA11><fA11 i1="08" i2="1"><s1>DONGLU BAI</s1></fA11><fA11 i1="09" i2="1"><s1>XICHANG HE</s1></fA11><fA11 i1="10" i2="1"><s1>LUDEWIG (Burkhard)</s1></fA11><fA11 i1="11" i2="1"><s1>JING CHEN</s1></fA11><fA11 i1="12" i2="1"><s1>HAIBIN LUO</s1></fA11><fA11 i1="13" i2="1"><s1>YIMING YANG</s1></fA11><fA11 i1="14" i2="1"><s1>YIFU YANG</s1></fA11><fA11 i1="15" i2="1"><s1>JIANPING ZOU</s1></fA11><fA11 i1="16" i2="1"><s1>THIEL (Volker)</s1></fA11><fA11 i1="17" i2="1"><s1>KAIXIAN CHEN</s1></fA11><fA11 i1="18" i2="1"><s1>JIANHUA SHEN</s1></fA11><fA11 i1="19" i2="1"><s1>XU SHEN</s1></fA11><fA11 i1="20" i2="1"><s1>HUALIANG JIANG</s1></fA11><fA14 i1="01"><s1>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</s1><s2>Shanghai 201203</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>17 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></fA14><fA14 i1="02"><s1>Department of Virology, Bemhard Nocht Institute for Tropical Medicine, Bemhard-Nocht-Str. 74</s1><s2>20359 Hamburg</s2><s3>DEU</s3><sZ>5 aut.</sZ><sZ>7 aut.</sZ></fA14><fA14 i1="03"><s1>Research Department, Kantonal Hospital St. Gallon</s1><s2>9007 St. Gallen</s2><s3>CHE</s3><sZ>6 aut.</sZ><sZ>10 aut.</sZ><sZ>16 aut.</sZ></fA14><fA14 i1="04"><s1>School of Pharmacy, East China University of Science and Technology</s1><s2>Shanghai 200237</s2><s3>CHN</s3><sZ>20 aut.</sZ></fA14><fA20><s1>7095-7103</s1></fA20><fA21><s1>2005</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>13592</s2><s5>354000125436420540</s5></fA43><fA44><s0>0000</s0><s1>© 2005 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>57 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>05-0248689</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>Journal of virology</s0></fA64><fA66 i1="01"><s0>USA</s0></fA66><fC01 i1="01" l="ENG"><s0>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.</s0></fC01><fC02 i1="01" i2="X"><s0>002A05C10</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>Coronavirus</s0><s2>NW</s2><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>Coronavirus</s0><s2>NW</s2><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>Coronavirus</s0><s2>NW</s2><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Peptidases</s0><s2>FE</s2><s5>05</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Peptidases</s0><s2>FE</s2><s5>05</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Peptidases</s0><s2>FE</s2><s5>05</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>Replication in vitro</s0><s5>06</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>In vitro replication</s0><s5>06</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>Replicación in vitro</s0><s5>06</s5></fC03><fC03 i1="04" i2="X" l="FRE"><s0>Microbiologie</s0><s5>07</s5></fC03><fC03 i1="04" i2="X" l="ENG"><s0>Microbiology</s0><s5>07</s5></fC03><fC03 i1="04" i2="X" l="SPA"><s0>Microbiología</s0><s5>07</s5></fC03><fC03 i1="05" i2="X" l="FRE"><s0>Virologie</s0><s5>08</s5></fC03><fC03 i1="05" i2="X" l="ENG"><s0>Virology</s0><s5>08</s5></fC03><fC03 i1="05" i2="X" l="SPA"><s0>Virología</s0><s5>08</s5></fC03><fC03 i1="06" i2="X" l="FRE"><s0>Cinansérine</s0><s2>NK</s2><s2>FR</s2><s5>14</s5></fC03><fC03 i1="06" i2="X" l="ENG"><s0>Cinanserin</s0><s2>NK</s2><s2>FR</s2><s5>14</s5></fC03><fC03 i1="06" i2="X" l="SPA"><s0>Cinanserina</s0><s2>NK</s2><s2>FR</s2><s5>14</s5></fC03><fC03 i1="07" i2="X" l="FRE"><s0>Syndrome respiratoire aigu sévère</s0><s2>NM</s2><s5>15</s5></fC03><fC03 i1="07" i2="X" l="ENG"><s0>Severe acute respiratory syndrome</s0><s2>NM</s2><s5>15</s5></fC03><fC03 i1="07" i2="X" l="SPA"><s0>Síndrome respiratorio agudo severo</s0><s2>NM</s2><s5>15</s5></fC03><fC07 i1="01" i2="X" l="FRE"><s0>Coronaviridae</s0><s2>NW</s2></fC07><fC07 i1="01" i2="X" l="ENG"><s0>Coronaviridae</s0><s2>NW</s2></fC07><fC07 i1="01" i2="X" l="SPA"><s0>Coronaviridae</s0><s2>NW</s2></fC07><fC07 i1="02" i2="X" l="FRE"><s0>Nidovirales</s0><s2>NW</s2></fC07><fC07 i1="02" i2="X" l="ENG"><s0>Nidovirales</s0><s2>NW</s2></fC07><fC07 i1="02" i2="X" l="SPA"><s0>Nidovirales</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="FRE"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="ENG"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="SPA"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="04" i2="X" l="FRE"><s0>Hydrolases</s0><s2>FE</s2></fC07><fC07 i1="04" i2="X" l="ENG"><s0>Hydrolases</s0><s2>FE</s2></fC07><fC07 i1="04" i2="X" l="SPA"><s0>Hydrolases</s0><s2>FE</s2></fC07><fC07 i1="05" i2="X" l="FRE"><s0>Enzyme</s0><s2>FE</s2></fC07><fC07 i1="05" i2="X" l="ENG"><s0>Enzyme</s0><s2>FE</s2></fC07><fC07 i1="05" i2="X" l="SPA"><s0>Enzima</s0><s2>FE</s2></fC07><fC07 i1="06" i2="X" l="FRE"><s0>Appareil respiratoire pathologie</s0><s5>13</s5></fC07><fC07 i1="06" i2="X" l="ENG"><s0>Respiratory disease</s0><s5>13</s5></fC07><fC07 i1="06" i2="X" l="SPA"><s0>Aparato respiratorio patología</s0><s5>13</s5></fC07><fC07 i1="07" i2="X" l="FRE"><s0>Virose</s0></fC07><fC07 i1="07" i2="X" l="ENG"><s0>Viral disease</s0></fC07><fC07 i1="07" i2="X" l="SPA"><s0>Virosis</s0></fC07><fC07 i1="08" i2="X" l="FRE"><s0>Infection</s0></fC07><fC07 i1="08" i2="X" l="ENG"><s0>Infection</s0></fC07><fC07 i1="08" i2="X" l="SPA"><s0>Infección</s0></fC07><fC07 i1="09" i2="X" l="FRE"><s0>Poumon pathologie</s0><s5>16</s5></fC07><fC07 i1="09" i2="X" l="ENG"><s0>Lung disease</s0><s5>16</s5></fC07><fC07 i1="09" i2="X" l="SPA"><s0>Pulmón patología</s0><s5>16</s5></fC07><fN21><s1>171</s1></fN21><fN44 i1="01"><s1>OTO</s1></fN44><fN82><s1>OTO</s1></fN82></pA></standard></inist></record>Pour manipuler ce document sous Unix (Dilib)
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|texte= Cinanserin is an inhibitor of the 3C-like proteinase of severe acute respiratory syndrome coronavirus and strongly reduces virus replication in vitro
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