Hepatitis C virus replication is inhibited by 22β-methoxyolean-12-ene-3β, 24(4β)-diol (ME3738) through enhancing interferon-β

Hiasa, Yoichi; Kuzuhara, Hiroyoshi; Terada, Yoshio; Konishi, Ichiro; Yamashita, Nobuyuki; Matsuura, Bunzo; Michitaka, Kojiro; Chung, Raymond T.; Onji, Morikazu

doi:10.1002/hep.22289

Cited by 9 publications

(9 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is probably due to a defect of the innate immune system in producing IFN-b in those cells. This is consistent with their finding that ME3738 had an inferior effect in Huh7 cells than in HepG2 cells to produce ISG products [13].…”

Section: Discussionsupporting

confidence: 90%

“…The extent of the increase in ISG expression was smaller in Hiasa et al [13] than in our results. This is probably because they used the T7-genotype 1a-cDNA transient transfection-infection system to produce HCV in HepG2 or Huh7 cells [13,24,25] and assessed the effect of ME3738 by utilizing naturally produced IFN-b. The amount of IFN is likely to be very small in their system compared to that used in our study.…”

Section: Discussioncontrasting

confidence: 78%

“…1A). Hiasa et al reported that ME3738 enhanced the expression of IFN-b mRNA and that the enhanced production of IFN-b resulted in the increased expression of ISGs [13]. They showed also that the effect of ME3738 on HCV was abolished following the inhibition of IFN-b expression with siRNA or antibody.…”

Section: Discussionmentioning

confidence: 96%

“…Furthermore, Hiasa et al reported recently that ME3738 induces IFN-b mRNA expression and inhibits the replication of HCV [13]. We thus attempted in this study to evaluate the effect of ME3738, especially in combination with IFN-a, on HCV.…”

Section: Discussionmentioning

confidence: 97%

See 3 more Smart Citations

ME3738 enhances the effect of interferon and inhibits hepatitis C virus replication both in vitro and in vivo

Abe

Imamura

Hiraga

et al. 2011

Journal of Hepatology

Self Cite

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 90%

Section: Discussioncontrasting

confidence: 78%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 97%

See 2 more Smart Citations

ME3738 enhances the effect of interferon and inhibits hepatitis C virus replication both in vitro and in vivo

Abe

Imamura

Hiraga

et al. 2011

Journal of Hepatology

Self Cite

View full text Add to dashboard Cite

“…These findings suggest that the anti-HCV and ␣-IFN enhancer effects are distinctive features of TSN among triterpenoid compounds. Hiasa et al have reported that ME3738, a triterpenoid saponin, suppressed HCV replication through production of endogenous beta interferon (11). ME3738 is now in clinical trials for treatment of HCVinfected patients.…”

Section: Discussionmentioning

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

View full text Add to dashboard Cite

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

show abstract

High Serum Palmitic Acid is Associated with Low Antiviral Effects of Interferon‐Based Therapy for Hepatitis C Virus

Miyake¹,

Hiasa²,

Hirooka³

et al. 2012

Lipids

View full text Add to dashboard Cite

Hepatitis C virus (HCV) infection alters fatty acid synthesis and metabolism in association with HCV replication. The present study examined the effect of serum fatty acid composition on interferon (IFN)-based therapy. Fifty-five patients with HCV were enrolled and received IFN-based therapy. Patient characteristics, laboratory data (including fatty acids), and viral factors that could be associated with the anti-HCV effects of IFN-based therapy were evaluated. The effects of individual fatty acids on viral replication and IFN-based therapy were also examined in an in-vitro system. Multivariate logistic regression analysis showed that the level of serum palmitic acid before treatment and HCV genotype were significant predictors for rapid virological response (RVR), early virological response (EVR), and sustained virological response (SVR). High levels of palmitic acid inhibited the anti-HCV effects of IFN-based therapy. HCV replication assays confirmed the inhibitory effects of palmitic acid on anti-HCV therapy. The concentration of serum palmitic acid is an independent predictive factor for RVR, EVR, and SVR in IFN-based antiviral therapy. These results suggest that the effect of IFN-based antiviral therapy in patients with HCV infection might be enhanced by treatment that modulates palmitic acid levels.

show abstract

Hepatitis C virus replication is inhibited by 22β-methoxyolean-12-ene-3β, 24(4β)-diol (ME3738) through enhancing interferon-β

Cited by 9 publications

References 36 publications

ME3738 enhances the effect of interferon and inhibits hepatitis C virus replication both in vitro and in vivo

ME3738 enhances the effect of interferon and inhibits hepatitis C virus replication both in vitro and in vivo

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

High Serum Palmitic Acid is Associated with Low Antiviral Effects of Interferon‐Based Therapy for Hepatitis C Virus

Contact Info

Product

Resources

About