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

Abstract

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

Determination of toosendanin in rat plasma by ultra‐performance liquid chromatography–electrospray ionization–mass spectrometry and its application in a pharmacokinetic study

“…Previous studies have indicated that it is a selective presynaptic blocking agent (Shi et al ., ; Shi and Sun, ) and also effective in inhibiting botulism (Shi and Li, ; Shi and Wang, ). Additionally, it was demonstrated that TSN could inhibit hepatitis C virus infection by a marked suppression of HCV RNA replication (Watanabe et al ., ), and suppress proliferation of various human cancer cell lines (Shi and Tang, ; Zhang et al ., ). Therefore it may be a promising lead compound for treating botulism and cancer.…”

Determination of toosendanin and trans‐anethole in Fructus Meliae Toosendan and Fructus Foeniculi by HPLC–MS/MS and GC–MS/MS in rat plasma and their potential herb–herb interactions

“…CLZ is known to have pharmacological properties, including antibacterial, antivirus, anti‐neuraminidase, antioxidant, anticancer, anti‐inflammatory and analgesic activities (Liu et al, 2016; X.‐L. Tang et al, 2012; L. Wang et al, 2014; Watanabe et al, 2011; Xie et al, 2008; Xu, Yu, Wang, Xu, & Liu, 2018). However, it has been frequently reported to induce severe liver injury during clinical practice and empirical research in recent years (Yang et al, 2019; Yuen et al, 2010; J. Zheng et al, 2015), and liver cell necrosis was proven to be the main liver toxicity mechanism of CLZ (J. Zheng et al, 2015; Jie Zheng, Yu, Chen, Lu, & Fan, 2018).…”

Toosendanin From Melia Fructus Suppresses Influenza A Virus Infection by Altering Nuclear Localization of Viral Polymerase PA Protein

“…In addition, TSN suppressed proliferation and induced apoptosis of human cancer cells (Zhang et al, 2005) and displayed anti-botulinum and anti-microbial activities as well as antifeedant and insecticide properties (Carpinella et al, 2003; Shi and Wang, 2004; Kamau et al, 2016). TSN also inhibited hepatitis C virus infection by enhancing alpha interferon (Watanabe et al, 2011). Another MF compound, 28-deacetylsendanin, inhibited the replication of herpes simplex virus-1 (Kim et al, 1999).…”