Abstract
Hepatitis C virus (HCV) is a causative agent of acute and chronic hepatitis, leading to the development of hepatic cirrhosis and hepatocellular carcinoma. We prepared extracts from 61 marine organisms and screened them by an in vitro fluorescence assay targeting the viral helicase (NS3), which plays an important role in HCV replication, to identify effective candidates for anti-HCV agents. An ethyl acetate-soluble fraction of the feather star Alloeocomatella polycladia exhibited the strongest inhibition of NS3 helicase activity, with an IC50 of 11.7 µg/mL. The extract of A. polycladia inhibited interaction between NS3 and RNA but not ATPase of NS3. Furthermore, the replication of the replicons derived from three HCV strains of genotype 1b in cultured cells was suppressed by the extract with an EC50 value of 23 to 44 µg/mL, which is similar to the IC50 value of the NS3 helicase assay. The extract did not induce interferon or inhibit cell growth. These results suggest that the unknown compound(s) included in A. polycladia can inhibit HCV replication by suppressing the helicase activity of HCV NS3. This study may present a new approach toward the development of a novel therapy for chronic hepatitis C.
Highlights
Hepatitis C virus (HCV) is an etiological agent of liver disease including steatosis, cirrhosis, and hepatocellular carcinoma, and has infected over 170 million individuals worldwide [1,2]
The EtOAc extract prepared from the feather star Alloeocomatella polycladia (Figure 2)
We confirmed the effect of SG1-23-1 on NS3 helicase unwinding activity by the RNA helicase assay using 32P-labeled double-stranded RNA as a substrate
Summary
Hepatitis C virus (HCV) is an etiological agent of liver disease including steatosis, cirrhosis, and hepatocellular carcinoma, and has infected over 170 million individuals worldwide [1,2]. Helicase as well as protease activities of NS3 can be targeted for use in the development of antiviral agents against HCV. Biotechnological advances of the past decade have led to the development of novel therapies using anti-HCV agents that directly target HCV proteins or host factors required for HCV replication. This approach has been named either “ targeted antiviral therapy for hepatitis C” (STAT-C) or “directed-acting antiviral agents”. The helicase activity of NS3 could be targeted by development of anti-HCV compound in addition to its protease activity. Marine organisms including plants and animals were recently established as a representative natural resource library for drug development, since there are estimated to be more than 300,000. The marine feather star Alloeocomatella polycladia may produce anti-HCV helicase agents that suppress HCV replication
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