UK-1 and structural analogs are potent inhibitors of hepatitis C virus replication |
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| Affiliation: | 1. Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, United States;2. Department of Molecular Biology, John Paul II Catholic University of Lublin, Poland;1. School of Life Science and Biotechnology, China Pharmaceutical University, Nanjing 210009, Jiangsu, China;2. VARI/SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;3. Laboratory of Structural Sciences, Program on Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA;1. Key Laboratory of Carbohydrate and Lipid Metabolism Research, College of Life Science and Technology, Dalian University, 10-Xuefu Avenue, Dalian Economical and Technological Development Zone, Dalian, Liaoning 116622, China;2. Department of Cell Chemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan;3. Biomedical Engineering Department, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3107, USA;1. Department of Pharmacy and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine & New Drug Research, Jinan University, Guangzhou 510632, China;2. Department of Analytical Chemistry, Physical Chemistry and Chemical Engineering, Faculty of Biology, Environmental Sciences and Chemistry, University of Alcalá, Ctra. Madrid—Barcelona, Km. 33.600, Alcalá de Henares, 28871 Madrid, Spain;3. Laboratory of Analytical Pharmaceutical Chemistry, Department of Pharmaceutical Sciences, University of Liege, CHU B36, B-4000 Liege, Belgium;1. G.K. Boreskov Institute of Catalysis, SB RAS, Acad. Lavrentjev Ave. 5, 630090 Novosibirsk, Russian Federation;2. N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, SB RAS, Acad. Lavrentjev Ave. 9, 630090 Novosibirsk, Russian Federation |
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| Abstract: | The bacterial natural product UK-1 and several structural analogs inhibit replication of the hepatitis C virus in the replicon assay, with IC50 values as low as 0.50 μM. The NS3 helicase has been identified as a possible target of inhibition for several of these compounds, while the remaining inhibitors act via an undetermined mechanism. Gel shift assays suggest that helicase inhibition is a direct result of inhibitor–enzyme binding as opposed to direct RNA binding, and the ATPase activity of NS3 is not affected. The syntheses and biological results are presented herein. |
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| Keywords: | Hepatitis C NS3 Helicase Inhibitor |
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