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

Abe, Hiromi; Imamura, Michio; Hiraga, Nobuhiko; Tsuge, Masataka; Mitsui, Fukiko; Kawaoka, Tomokazu; Takahashi, Shoichi; Ochi, Hidenori; Maekawa, Toshiro; Hayes, C. Nelson; Tateno, Chise; Yoshizato, Katsutoshi; Murakami, Shoichi; Yamashita, Nobuyuki; Matsuhira, Takashi; Asai, Kenji; Chayama, Kazuaki

doi:10.1016/j.jhep.2010.10.017

Cited by 9 publications

(7 citation statements)

References 28 publications

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“…Entry inhibitors typically should not affect established infection when used alone in vivo. However, the in vivo antiviral effect of CCZ on preexisting steady-state infection in mice is similar to that of IFN-a (31). It is known that in vivo, circulating HCV has a very short T 1/2 (32), HCV-infected hepatocytes may turnover quickly, and the newly produced virus probably continues to infect uninfected hepatocytes (33).…”

Section: Discussionmentioning

confidence: 98%

Repurposing of the antihistamine chlorcyclizine and related compounds for treatment of hepatitis C virus infection

et al. 2015

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Hepatitis C virus (HCV) infection affects an estimated 185 million people worldwide, with chronic infection often leading to liver cirrhosis and hepatocellular carcinoma. Although HCV is curable, there is an unmet need for the development of effective and affordable treatment options. Through a cell-based high-throughput screen, we identified chlorcyclizine HCl (CCZ), an over-the-counter drug for allergy symptoms, as a potent inhibitor of HCV infection. CCZ inhibited HCV infection in human hepatoma cells and primary human hepatocytes. The mode of action of CCZ is mediated by inhibiting an early stage of HCV infection, probably targeting viral entry into host cells. The in vitro antiviral effect of CCZ was synergistic with other anti-HCV drugs, including ribavirin, interferon-α, telaprevir, boceprevir, sofosbuvir, daclatasvir, and cyclosporin A, without significant cytotoxicity, suggesting its potential in combination therapy of hepatitis C. In the mouse pharmacokinetic model, CCZ showed preferential liver distribution. In chimeric mice engrafted with primary human hepatocytes, CCZ significantly inhibited infection of HCV genotypes 1b and 2a, without evidence of emergence of drug resistance, during 4 and 6 weeks of treatment, respectively. With its established clinical safety profile as an allergy medication, affordability, and a simple chemical structure for optimization, CCZ represents a promising candidate for drug repurposing and further development as an effective and accessible agent for treatment of HCV infection.

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Section: Discussionmentioning

confidence: 98%

Repurposing of the antihistamine chlorcyclizine and related compounds for treatment of hepatitis C virus infection

et al. 2015

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“…In vitro assay, 35 reduces HCV core antigen (HCVcAg) and HCV-RNA levels in mouse livers. 92 Moreover, ME 3738 was also found to be an inducer of interleukin 6 (IL-6). It can stimulate the production of IL-6 and protect mouse from acute liver injury/failure induced by concanavalin A (Con A) and prevent the development of alcoholic fatty liver.…”

Section: Immunomodulatormentioning

confidence: 99%

Recent progress in the antiviral activity and mechanism study of pentacyclic triterpenoids and their derivatives

Xiao

Tian

Wang

et al. 2018

Medicinal Research Reviews

152

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Viral infections cause many serious human diseases with high mortality rates. New drug-resistant strains are continually emerging due to the high viral mutation rate, which makes it necessary to develop new antiviral agents. Compounds of plant origin are particularly interesting. The pentacyclic triterpenoids (PTs) are a diverse class of natural products from plants composed of three terpene units. They exhibit antitumor, anti-inflammatory, and antiviral activities. Oleanolic, betulinic, and ursolic acids are representative PTs widely present in nature with a broad antiviral spectrum. This review focuses on the recent literatures in the antiviral efficacy of this class of phytochemicals and their derivatives. In addition, their modes of action are also summarized.

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“…Hepatocellular carcinoma (HCC) is one of the most common cancer types worldwide and a leading cause of cancer mortality, especially in countries with a high prevalence of chronic infections with hepatitis B virus and hepatitis C virus (HCV). ME3738 suppresses HCV replication by inhibiting mRNA in HCV replicon cells, along with NS3 and core proteins (14). Saibara et al treated chronic hepatitis C patients for 48 weeks with a combination of PEG interferon (IFN)-α-2b and ME3738 (15).…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative effect of ME3738, a derivative of soyasapogenol, on hepatocellular carcinoma cell lines in vitro and in vivo

et al. 2016

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Soyasapogenol, an aglycon of soyasaponin, ameliorates liver injury induced by concanavalin A in mice. A derivative of soyasapogenol, 22β-methoxyolean-12-ene-3β, 24(4β)-diol (ME3738), was reported to induce the gene expression of interferon (IFN)-β in hepatitis C virus replicon cells. The effect of ME3738 on hepatocellular carcinoma (HCC) cell lines was investigated in the present study. A total of 11 HCC cell lines were cultured in medium containing 0-10 µM ME3738, and after 24, 48, or 72 h of culture, morphological observation and MTT cell growth assays were performed. Furthermore, the effects of ME3738 with or without PEG-IFN-α-2b on cell lines were investigated. Induction of apoptosis was examined on cells treated with 1 µM of ME3738 using an Annexin V assay. The effect of ME3738 (0.63 and 2.5 µM) on cell cycle progression was analyzed on two cell lines. The mice with subcutaneous tumors were divided into four groups: i) Control; ii) ME3738 alone; iii) PEG-IFN-α-2b alone and iv) ME3738+PEG-IFN-α-2b (combination). ME3738 was mixed with food (1.5 mg/g) and was taken orally for 15 days. PEG-IFN-α-2b (1,920 IU/mouse) was subcutaneously injected twice a week for two consecutive weeks. On day 15, the mice were sacrificed and the tumors were resected. A dose-dependent anti-proliferative effect was observed to various degrees in all the HCC cell lines in vitro. This inhibitory effect reached its maximal level 24 h after the treatment and the 50% inhibitory dose was between 0.8 and 2.4 µM. The combination treatment did not show a synergistic effect. Induction of apoptosis was not observed. Cell cycle arrest at S-phase was observed in two of the examined cell lines. On day 15, the tumor volume of mice receiving ME3738, PEG-IFN-α-2b, and ME3738+PEG-IFN-α-2b was 69, 30, and 33%, respectively, of the control tumor volume. ME3738 induced antiproliferative effects on the HCC cells in vitro and in vivo. The data suggested potential clinical application of ME3738.

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

Cited by 9 publications

References 28 publications

Repurposing of the antihistamine chlorcyclizine and related compounds for treatment of hepatitis C virus infection

Repurposing of the antihistamine chlorcyclizine and related compounds for treatment of hepatitis C virus infection

Recent progress in the antiviral activity and mechanism study of pentacyclic triterpenoids and their derivatives

Antiproliferative effect of ME3738, a derivative of soyasapogenol, on hepatocellular carcinoma cell lines in vitro and in vivo

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