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A novel anti-hepatitis B virus regent iCDM-34 reveals suppression of cccDNA accompanied with aryl hydrocarbon receptor activation

ABSTRACT: Background & Aims: IFN-alpha and -gamma have been reported to suppress cccDNA via APOBEC3 cytidine deaminase activity, and CDM-3008, an IFNAR2 agonist, also suppress cccDNA through interferon signaling. In order to develop a novel anti-HBV drug for functional or complete cure, we performed in silico screening using a structure of CDM-3008-binding pocket in IFNAR2. Approach & Results: The binding pocket of CDM-3008 in IFNAR2 was determined by LC-MS/MS using a CDM-3008-based molecular probe, CDM-3095 and a recombinant protein of IFNAR2 extracellular region. We conducted in silico screening of the binding compounds fitting the steric structure of the pocket. We identified 37 compounds and named them iCDM-1–37. We found that iCDM-34 showed anti-HCV and anti-HBV activities. We measured the anti-HBV activity of iCDM-34 with or without entecavir (ETV). iCDM-34 suppressed pregenome RNA, covalently closed circular DNA (cccDNA), HBsAg, and HBeAg and clearly exhibited synergistic inhibitory effects with ETV. Metabolic stability of iCDM-34 was measured in human, mouse, and rat microsomal fractions. iCDM-34 was stable in human liver microsomal fraction. Furthermore, anti-HBV activity in human hepatocyte-chimeric mice revealed that iCDM-34 was not effective as a single agent, but when combined with ETV, it suppressed HBV DNA and cccDNA compared to ETV alone. Phosphoproteome analysis showed no activation of IFN signaling with iCDM-34 treatment. Transcriptome analysis of interferon-stimulated genes (ISGs) revealed no increase in the expression, while downstream factors of aryl hydrocarbon receptor (AhR) showed increased expression. Conclusion: iCDM-34 is a novel anti-HBV drug that induces AhR activation and suppresses cccDNA. Conclusion: iCDM-34 is a novel anti-HBV drug that induces AhR activation and suppresses cccDNA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE180646 | GEO | 2022/03/25

REPOSITORIES: GEO

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Project description:Oral administration of nucleotide analogues and injection of interferon-alpha (IFNalpha) are used to achieve immediate suppression in replication of hepatitis B virus (HBV). Nucleotide analogs and IFNalpha inhibit viral polymerase activity and cause long-term eradication of the virus at least in part through removing covalently closed circular DNA (cccDNA) via induction of the APOBEC3 deaminases family of molecules, respectively. This study aimed to explore whether the orally administrable low molecular weight agent CDM-3008 (RO8191), which mimics IFNalpha through the binding to IFNalpha receptor 2 (IFNAR2) and the activation of the JAK/STAT pathway, can suppress HBV replication and reduce cccDNA levels. In primary cultured human hepatocytes, HBV DNA levels as well as cccDNA levels were decreased after CDM-3008-treatment in a dose-dependent manner with a half-maximal inhibitory concentration (IC50) value of 0.1 micro M, and this was accompanied by significant reductions in both HBeAg and HBsAg levels in the cell culture medium. Using a microarray we comprehensively analyzed and compared changes in gene (mRNA) expression in CDM-3008- and IFNalpha-treated primary cultured human hepatocytes. As reported previously, CDM-3008 mimicked the induction of　molecules that participate in the interferon signaling pathway. OAS1 and ISG20 mRNA expression was similarly enhanced by both CDM-3008 and IFNalpha. Thus, CDM-3008 could suppress pgRNA expression to show anti-HBV activity. APOBEC3F and 3G mRNA expression was induced by CDM-3008 and IFNalpha treatment suggesting that cccDNA could be degraded through induced APOBEC3 family proteins. Finally, we identified the genes whose expression was specifically enhanced in CDM-3008-treated cells compared to IFNalpha-treated cells. The expression of SOCS1, SOCS2, SOCS3, and CISH, which inhibit STAT activation, was enhanced in CDM-3008-treated cells suggesting that a feedback inhibition of the JAK/STAT pathway was enhanced in CDM-3008-treated cells compared to IFNalpha-treated cells. In addition, CDM-3008 showed an additive effect with entecavir on inhibition of HBV replication. In summary, CDM-3008 showed anti-HBV activity through activation of the JAK/STAT pathway, inducing the expression of interferon-stimulated genes (ISGs), with greater feedback inhibition than IFNalpha.

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A novel anti-hepatitis B virus regent iCDM-34 reveals suppression of cccDNA accompanied with aryl hydrocarbon receptor activation

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