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

Lili Chen,^1, Chunshan Gui,^1, Xiaomin Luo,^1, Qingang Yang,^1, 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 Jiang^1,4

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 (3CL^pro) 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^pro. 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^pro 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.

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

These authors contributed equally to this work.

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