Comprehensive Medicinal Chemistry (CMC)

Cinanserin is an inhibitor of the 3C-like proteinase of severe acute respiratory syndrome coronavirus and strongly reduces virus replication in vitro

Chen, L.^a , Gui, C.^a , Luo, X.^a , Yang, Q.^a , Günther, S.^b , Scandella, E.^c , Drosten, C.^b , Bai, D.^a , He, X.^a , Ludewig, B.^c , Chen, J.^a , Luo, H.^a , Yang, Y.^a , Yang, Y.^a , Zou, J.^a , Thiel, V.^c , Chen, K.^a , Shen, J.^a , Shen, X.^a , Jiang, H.^{a d}

^a State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
^b Department of Virology, Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Str. 74, 20359 Hamburg, Germany
^c Research Department, Kantonal Hospital St. Gallen, CH-9007 St. Gallen, Switzerland
^d School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China

Abstract

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. Copyright © 2005, American Society for Microbiology. All Rights Reserved.