Small molecules targeting severe acute respiratory syndrome human coronavirus
Chung‐Yi WuGenomics Research Center and Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Preventive Medicine, National Defense Medical Center, National Defense University, Taipei 114, Taiwan; Department of Chemical Engineering, National Taipei University of Technology, Taipei 106, Taiwan; Department of Chemistry, National Taiwan University, Taipei 106, Taiwan; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CAJia-Tsrong JanGenomics Research Center and Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Preventive Medicine, National Defense Medical Center, National Defense University, Taipei 114, Taiwan; Department of Chemical Engineering, National Taipei University of Technology, Taipei 106, Taiwan; Department of Chemistry, National Taiwan University, Taipei 106, Taiwan; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CAShiou-Hwa MaGenomics Research Center and Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Preventive Medicine, National Defense Medical Center, National Defense University, Taipei 114, Taiwan; Department of Chemical Engineering, National Taipei University of Technology, Taipei 106, Taiwan; Department of Chemistry, National Taiwan University, Taipei 106, Taiwan; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CAChih‐Jung KuoGenomics Research Center and Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Preventive Medicine, National Defense Medical Center, National Defense University, Taipei 114, Taiwan; Department of Chemical Engineering, National Taipei University of Technology, Taipei 106, Taiwan; Department of Chemistry, National Taiwan University, Taipei 106, Taiwan; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CAHsueh‐Fen JuanGenomics Research Center and Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Preventive Medicine, National Defense Medical Center, National Defense University, Taipei 114, Taiwan; Department of Chemical Engineering, National Taipei University of Technology, Taipei 106, Taiwan; Department of Chemistry, National Taiwan University, Taipei 106, Taiwan; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CAYih‐Shyun E. ChengGenomics Research Center and Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Preventive Medicine, National Defense Medical Center, National Defense University, Taipei 114, Taiwan; Department of Chemical Engineering, National Taipei University of Technology, Taipei 106, Taiwan; Department of Chemistry, National Taiwan University, Taipei 106, Taiwan; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CAHsien-Hua HsuGenomics Research Center and Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Preventive Medicine, National Defense Medical Center, National Defense University, Taipei 114, Taiwan; Department of Chemical Engineering, National Taipei University of Technology, Taipei 106, Taiwan; Department of Chemistry, National Taiwan University, Taipei 106, Taiwan; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CAHsuan‐Cheng HuangInstitute of Preventive Medicine, National Defense Medical Center, National Defense University, Taipei 114, TaiwanDouglass WuGenomics Research Center and Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Preventive Medicine, National Defense Medical Center, National Defense University, Taipei 114, Taiwan; Department of Chemical Engineering, National Taipei University of Technology, Taipei 106, Taiwan; Department of Chemistry, National Taiwan University, Taipei 106, Taiwan; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CAAshraf BrikGenomics Research Center and Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Preventive Medicine, National Defense Medical Center, National Defense University, Taipei 114, Taiwan; Department of Chemical Engineering, National Taipei University of Technology, Taipei 106, Taiwan; Department of Chemistry, National Taiwan University, Taipei 106, Taiwan; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CAFu‐Sen LiangGenomics Research Center and Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Preventive Medicine, National Defense Medical Center, National Defense University, Taipei 114, Taiwan; Department of Chemical Engineering, National Taipei University of Technology, Taipei 106, Taiwan; Department of Chemistry, National Taiwan University, Taipei 106, Taiwan; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CARai-Shung LiuGenomics Research Center and Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Preventive Medicine, National Defense Medical Center, National Defense University, Taipei 114, Taiwan; Department of Chemical Engineering, National Taipei University of Technology, Taipei 106, Taiwan; Department of Chemistry, National Taiwan University, Taipei 106, Taiwan; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CAJim‐Min FangGenomics Research Center and Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Preventive Medicine, National Defense Medical Center, National Defense University, Taipei 114, Taiwan; Department of Chemical Engineering, National Taipei University of Technology, Taipei 106, Taiwan; Department of Chemistry, National Taiwan University, Taipei 106, Taiwan; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CAShui-Tein ChenGenomics Research Center and Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Preventive Medicine, National Defense Medical Center, National Defense University, Taipei 114, Taiwan; Department of Chemical Engineering, National Taipei University of Technology, Taipei 106, Taiwan; Department of Chemistry, National Taiwan University, Taipei 106, Taiwan; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CAPo‐Huang LiangGenomics Research Center and Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Preventive Medicine, National Defense Medical Center, National Defense University, Taipei 114, Taiwan; Department of Chemical Engineering, National Taipei University of Technology, Taipei 106, Taiwan; Department of Chemistry, National Taiwan University, Taipei 106, Taiwan; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CAChi‐Huey WongGenomics Research Center and Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Preventive Medicine, National Defense Medical Center, National Defense University, Taipei 114, Taiwan; Department of Chemical Engineering, National Taipei University of Technology, Taipei 106, Taiwan; Department of Chemistry, National Taiwan University, Taipei 106, Taiwan; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA
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Аннотация
Severe acute respiratory syndrome (SARS) is an infectious disease caused by a novel human coronavirus. Currently, no effective antiviral agents exist against this type of virus. A cell-based assay, with SARS virus and Vero E6 cells, was developed to screen existing drugs, natural products, and synthetic compounds to identify effective anti-SARS agents. Of >10,000 agents tested, approximately 50 compounds were found active at 10 microM; among these compounds, two are existing drugs (Reserpine 13 and Aescin 5) and several are in clinical development. These 50 active compounds were tested again, and compounds 2-6, 10, and 13 showed active at 3 microM. The 50% inhibitory concentrations for the inhibition of viral replication (EC(50)) and host growth (CC(50)) were then measured and the selectivity index (SI = CC(50)/EC(50)) was determined. The EC(50), based on ELISA, and SI for Reserpine, Aescim, and Valinomycin are 3.4 microM (SI = 7.3), 6.0 microM (SI = 2.5), and 0.85 microM (SI = 80), respectively. Additional studies were carried out to further understand the mode of action of some active compounds, including ELISA, Western blot analysis, immunofluorescence and flow cytometry assays, and inhibition against the 3CL protease and viral entry. Of particular interest are the two anti-HIV agents, one as an entry blocker and the other as a 3CL protease inhibitor (K(i) = 0.6 microM).
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