Abstract
Hepatitis C virus (HCV) is an important etiological agent that is responsible for the development of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. HCV nonstructural protein 3 (NS3) helicase is a possible target for novel drug development due to its essential role in viral replication. In this study, we identified halisulfate 3 (hal3) and suvanine as novel NS3 helicase inhibitors, with IC50 values of 4 and 3 µM, respectively, from a marine sponge by screening extracts of marine organisms. Both hal3 and suvanine inhibited the ATPase, RNA binding, and serine protease activities of NS3 helicase with IC50 values of 8, 8, and 14 µM, and 7, 3, and 34 µM, respectively. However, the dengue virus (DENV) NS3 helicase, which shares a catalytic core (consisting mainly of ATPase and RNA binding sites) with HCV NS3 helicase, was not inhibited by hal3 and suvanine, even at concentrations of 100 µM. Therefore, we conclude that hal3 and suvanine specifically inhibit HCV NS3 helicase via an interaction with an allosteric site in NS3 rather than binding to the catalytic core. This led to the inhibition of all NS3 activities, presumably by inducing conformational changes.
Highlights
An estimated 150 million people worldwide are chronically infected with the hepatitis C virus (HCV), a major etiological agent responsible for the development of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (World Health Organization, 2013)
To obtain novel nonstructural protein 3 (NS3) helicase inhibitors, extracts from marine organisms were screened using a fluorescence helicase assay based on photoinduced electron transfer (PET)
Forty-three extracts prepared from marine organisms were screened, and 11 were identified that inhibited the helicase activity >50% (Table 1), suggesting that these extracts contained NS3 helicase inhibitors
Summary
An estimated 150 million people worldwide are chronically infected with the hepatitis C virus (HCV), a major etiological agent responsible for the development of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (World Health Organization, 2013). HCV nonstructural protein 3 (NS3) helicase has been considered as a novel antiviral target owing to its essential role in viral replication [5,6]. HCV NS3 helicase is part of the family of viral DExH proteins; the NS3/NPH-II family that encompasses helicases from positive-stranded RNA viruses [16,17,18]. These closely related helicases share a catalytic core that consists mainly of NTPase and nucleic acid binding sites, as well as many other structural and functional features. The chemical structure has been isolated for two of these compounds, whereas the remaining five are synthetic agents based on marine products. The inhibitory activities of hal and suvanine against DENV NS3 helicase were determined to characterize the binding sites of hal and suvanine
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