New therapeutic approaches to hepatitis C virus

Sakamoto, Naoya; Watanabe, Mamoru

doi:10.1007/s00535-009-0084-0

Cited by 32 publications

(26 citation statements)

References 68 publications

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“…Currently, the most efficient combination treatment of ribavirin plus peginterferon can eliminate the virus in almost half of the patients treated [2,3]. Thus, it is our high priority goal to understand the HCV life cycle precisely, to identify cellular cofactors for HCV replication and to develop new class antiviral therapeutics.…”

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confidence: 99%

Comparison of HCV-associated gene expression and cell signaling pathways in cells with or without HCV replicon and in replicon-cured cells

et al. 2009

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Section: Introductionmentioning

confidence: 99%

Comparison of HCV-associated gene expression and cell signaling pathways in cells with or without HCV replicon and in replicon-cured cells

et al. 2009

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“…Patients with minor variants of IL28B, who comprise ϳ50% of Caucasian, 25% of Asian, and ϳ70% of African populations, showed poor responses to ␣-IFN treatment. Although new specific anti-HCV drugs are under development, many of them require combined use with ␣-IFN and RBV (26). Taken together, current difficulties in eliminating HCV are mostly attributable to the limited treatment options and to the limited activity of ␣-IFN against the virus.…”

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confidence: 99%

Inhibitory Effect of a Triterpenoid Compound, with or without Alpha Interferon, on Hepatitis C Virus Infection

Watanabe

Sakamoto

Nakagawa

et al. 2011

Antimicrob Agents Chemother

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A lack of patient response to alpha interferon (␣-IFN) plus ribavirin (RBV) treatment is a major problem in eliminating hepatitis C virus (HCV). We screened chemical libraries for compounds that enhanced cellular responses to ␣-IFN and identified a triterpenoid, toosendanin (TSN).Hepatitis C virus (HCV) is one of the most important pathogens causing acute and chronic hepatitis, liver cirrhosis, and hepatocellular malignancies (29). Alpha interferon (␣-IFN) combined with ribavirin (RBV) is the standard treatment for HCV infection (6, 10). However, virus elimination rates are about 50% among treated patients, and therapy is often accompanied by substantial side effects (6, 44). It was recently reported that genetic polymorphisms of the IL28B gene, which codes for lambda IFN, are critical for predicting responses to ␣-IFN plus RBV therapy (8,35,38). Patients with minor variants of IL28B, who comprise ϳ50% of Caucasian, 25% of Asian, and ϳ70% of African populations, showed poor responses to ␣-IFN treatment. Although new specific anti-HCV drugs are under development, many of them require combined use with ␣- IFN and RBV (26). Taken together, current difficulties in eliminating HCV are mostly attributable to the limited treatment options and to the limited activity of ␣-IFN against the virus. For this reason, the development of safe and effective agents that enhance antiviral actions against HCV has been a strong motivation in academia and industry.To search for a new agent which enhances the effect of ␣-IFN, we used interferon-stimulated response element (ISRE) reporter screening. We screened a chemical library (60,500 compounds) for compounds that enhance ISRE activity when they are used in combination with ␣-IFN, using ISRE reporter screening, and identified several compounds that increased the ISRE reporter activities when they are used in combination with ␣-IFN and that did not show cytotoxicity. Among the hit compounds, toosendanin (TSN; C 30 H 38 O 11 ; molecular weight ϭ 574) (Fig. 1), which is a triterpenoid derivative extracted from the bark of Melia toosendan Sieb et Zucc, was the strongest in enhancing ␣-IFN-induced ISRE reporter activation and the expression of interferon-stimulated genes (ISGs). TSN has been used as an anthelmintic vermifuge against ascaris (31). Although TSN has some other biological effects against toxin-producing anaerobic bacteria and against carcinoma cells (32,45), antiviral activity has not been reported.In this study, we showed, using an HCV replicon system, that TSN, with or without ␣-IFN, inhibits HCV replication in a cultured human hepatoma Huh7 cell line and that the combination of TSN and ␣-IFN shows synergistic effects on viral replication. We have investigated the mechanisms of action of

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“…These difficulties in eradicating HCV are compounded by the limited treatment options. For this reason, the development of safe and effective therapeutic agents against HCV has been a strong motivation in academia and industry (23).…”

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Inhibition of Hepatitis C Virus Replication by a Specific Inhibitor of Serine-Arginine-Rich Protein Kinase

Karakama¹,

Sakamoto

Itsui

et al. 2010

Antimicrob Agents Chemother

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Splicing of messenger RNAs is regulated by site-specific binding of members of the serine-arginine-rich (SR) protein family, and SR protein kinases (SRPK) 1 and 2 regulate overall activity of the SR proteins by phosphorylation of their RS domains. We have reported that specifically designed SRPK inhibitors suppressed effectively several DNA and RNA viruses in vitro and in vivo. Here, we show that an SRPK inhibitor, SRPIN340, suppressed in a dose-dependent fashion expression of a hepatitis C virus (HCV) subgenomic replicon and replication of the HCV-JFH1 clone in vitro. The inhibitory effects were not associated with antiproliferative or nonspecific cytotoxic effects on the host cells. Overexpression of SRPK1 or SRPK2 resulted in augmentation of HCV replication, while small interfering RNA (siRNA) knockdown of the SRPKs suppressed HCV replication significantly. Immunocytochemistry showed that SRPKs and the HCV core and NS5A proteins colocalized to some extent in the perinuclear area. Our results demonstrate that SRPKs are host factors essential for HCV replication and that functional inhibitors of these kinases may constitute a new class of antiviral agents against HCV infection.Hepatitis C virus (HCV) infects up to 170 million people worldwide, and these infections frequently are characterized by chronic liver inflammation, leading to decompensated liver cirrhosis and hepatocellular cancers (1). Alpha and beta interferons are the mainstay of HCV therapeutics. However, the most effective pegylated interferon plus ribavirin combination therapies can eliminate HCV from around half of the patients only (6). These difficulties in eradicating HCV are compounded by the limited treatment options. For this reason, the development of safe and effective therapeutic agents against HCV has been a strong motivation in academia and industry (23).Serine-arginine-rich (SR) proteins are a family of non-small nuclear ribonucleoprotein particle (non-snRNP) splicing factors that are highly conserved throughout the eukaryotes. They harbor one or two RNA recognition motifs and an RS domain at the amino and carboxyl termini, respectively (29). RS domains consist of multiple consecutive Arg-Ser/Ser-Arg dipeptide repeats, in which the Ser residues are extensively phosphorylated by several kinases, including SR protein kinases (SRPKs). SRPK1 was the first SR protein kinase to be cloned, on the basis of its ability to phosphorylate SR proteins in vitro (8, 9), and two other structurally related kinases, SRPK2 and SRPK3, also have been shown to phosphorylate SR proteins (16,31). Although the precise physiological role of this phosphorylation remains unknown, it is expected that phosphorylation of SR proteins affects their protein-protein and protein-RNA interactions, intracellular localization and trafficking, and alternative splicing of pre-mRNA (21).As SRPK-dependent herpes simplex virus (HSV) splicing and SRPK-mediated phosphorylation of hepatitis B virus (HBV) core protein have been reported (4,25,33), it is reasonable to expect that SR...

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New therapeutic approaches to hepatitis C virus

Cited by 32 publications

References 68 publications

Comparison of HCV-associated gene expression and cell signaling pathways in cells with or without HCV replicon and in replicon-cured cells

Comparison of HCV-associated gene expression and cell signaling pathways in cells with or without HCV replicon and in replicon-cured cells

Inhibitory Effect of a Triterpenoid Compound, with or without Alpha Interferon, on Hepatitis C Virus Infection

Inhibition of Hepatitis C Virus Replication by a Specific Inhibitor of Serine-Arginine-Rich Protein Kinase

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