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Journal of Virology, June 2005, p. 7095-7103, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.7095-7103.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Cinanserin Is an Inhibitor of the 3C-Like Proteinase of Severe Acute Respiratory Syndrome Coronavirus and Strongly Reduces Virus Replication In Vitro{dagger}

Lili Chen,1,{ddagger} Chunshan Gui,1,{ddagger} Xiaomin Luo,1,{ddagger} Qingang Yang,1,{ddagger} Stephan Günther,2* Elke Scandella,3 Christian Drosten,2 Donglu Bai,1 Xichang He,1 Burkhard Ludewig,3 Jing Chen,1 Haibin Luo,1 Yiming Yang,1 Yifu Yang,1 Jianping Zou,1 Volker Thiel,3 Kaixian Chen,1 Jianhua Shen,1 Xu Shen,1* and Hualiang Jiang1,4

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,1 Department of Virology, Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Str. 74, 20359 Hamburg, Germany,2 Research Department, Kantonal Hospital St. Gallen, CH-9007 St. Gallen, Switzerland,3 School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China4

Received 22 October 2004/ Accepted 14 January 2005

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.

* 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: guenther{at}bni.uni-hamburg.de. 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: xshen{at}mail.shcnc.ac.cn.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

{ddagger} These authors contributed equally to this work.

Journal of Virology, June 2005, p. 7095-7103, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.7095-7103.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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