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Hepatitis C Virus NS3 Helicase Inhibitor Discovery.


Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-.
2011 Dec 16 [updated 2013 Mar 14].

Author information

University of Kansas Specialized Chemistry Center, University of Kansas, Lawrence, KS 66047
Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 N. Cramer St., Milwaukee, WI 53211
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595
Scripps Research Institute Molecular Screening Center, 10550 N. Torrey Pines Rd, La Jolla, CA 92037
Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, 66047


The Hepatitis C virus (HCV) is a major cause of liver failure and hepatocellular carcinoma, with about 170 million people infected worldwide. Replication of HCV in human cells requires the action of the HCV non-structural protein 3 (NS3), which exhibits both protease and helicase activities. Since there are numerous NS3 protease inhibitors but few NS3 helicase inhibitors, the goal here was to develop specific NS3 helicase inhibitors. During assay development, we discovered that trace components in the dye mixtures thioflavine S and primuline were potent inhibitors of the NS3 helicase. Based on the common structure of these components we designed ML283. The probe candidate is a potent inhibitor of the NS3 helicase enzyme and can be synthesized in the necessary quantities for further investigation. ML283 is more potent and specific than other recently reported NS3 helicase inhibitors under the same assay conditions, allowing a direct comparison. Preliminary experiments indicate that this compound is able to penetrate cells and inhibit HCV replication with no significant cytotoxicity. Thus the probe would be a useful tool for the investigation of viral helicases.

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