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Evans Blue Inhibits HBV Replication Through a Dual Antiviral Mechanism by Targeting Virus Binding and Capsid Assembly.

ABSTRACT: Chronic hepatitis B (CHB) is a global health problem caused by human hepatitis B virus (HBV). Current treatment with interferons and nucleos(t)ide analogs (NAs) can cause population tolerance and drug resistance. Therefore, new antiviral drugs, especially those targeting host factors, are urgently needed. Here, we identified Evans blue as a new HBV inhibitor by screening an FDA drug library using Huh7DhNTCP cells and confirmed the antiviral activity in primary human hepatocytes and human sodium taurocholate cotransporting polypeptide (hNTCP)-transfected porcine primary hepatocytes. Our efficacy study showed that Evans blue has an IC50 of 2 ?M against HBV infection in Huh7DhNTCP cells, and no apparent toxicity at up to 1000 ?M. The IC50 of Evans blue against HBV in primary human hepatocytes was approximately 5 ?M. Mechanism studies revealed that Evans blue has a dual anti-HBV effect. It inhibits both the binding of viral preS1 to host cells through the host factor NTCP and the virus capsid assembly by targeting the host factor BK channel. The KD of the direct interaction between Evans blue and NTCP is 8.82E-8 M. Evans blue can suppress capsid assembly at micromolar concentrations by reducing the cytosolic calcium ion concentration. Since the antiviral effects on HBV binding and assembly are both achieved through targeting host factors, Evans blue inhibits the infection of nucleos(t)ide analog drug-resistant HBV strains in Huh7DhNTCP cells. Taken together, our results suggest that Evans blue may be a promising anti-HBV drug candidate in the classes of both entry and assembly inhibitors.

SUBMITTER: Xiao Y

PROVIDER: S-EPMC6868041 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Evans Blue Inhibits HBV Replication Through a Dual Antiviral Mechanism by Targeting Virus Binding and Capsid Assembly.

Xiao Yu Y Liu Chunlan C Tang Wei W Zhang Haiwei H Chen Xulin X

Frontiers in microbiology 20191114

Chronic hepatitis B (CHB) is a global health problem caused by human hepatitis B virus (HBV). Current treatment with interferons and nucleos(t)ide analogs (NAs) can cause population tolerance and drug resistance. Therefore, new antiviral drugs, especially those targeting host factors, are urgently needed. Here, we identified Evans blue as a new HBV inhibitor by screening an FDA drug library using Huh7D<sup>hNTCP</sup> cells and confirmed the antiviral activity in primary human hepatocytes and hu ...[more]

PMID: 31798562

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Project description:BackgroundProgressive hepatitis B virus (HBV) infection can result in cirrhosis, hepatocellular cancer, and chronic hepatitis. While antiviral drugs that are now on the market are efficient in controlling HBV infection, finding a functional cure is still quite difficult. Identifying host factors involved in regulating the HBV life cycle will contribute to the development of new antiviral strategies. Zinc finger proteins have a significant function in HBV replication, according to earlier studies. Zinc finger protein 148 (ZNF148), a zinc finger transcription factor, regulates the expression of various genes by specifically binding to GC-rich sequences within promoter regions. The function of ZNF148 in HBV replication was investigated in this study.MethodsHepG2-Na+/taurocholate cotransporting polypeptide (HepG2-NTCP) cells and Huh7 cells were used to evaluate the function of ZNF148 in vitro. Northern blotting and real-time PCR were used to quantify the amount of viral RNA. Southern blotting and real-time PCR were used to quantify the amount of viral DNA. Viral protein levels were elevated, according to the Western blot results. Dual-luciferase reporter assays were used to examine the transcriptional activity of viral promoters. ZNF148's impact on HBV in vivo was investigated using an established rcccDNA mouse model.ResultsZNF148 overexpression significantly decreased the levels of HBV RNAs and HBV core DNA in HBV-infected HepG2-NTCP cells and Huh7 cells expressing prcccDNA. Silencing ZNF148 exhibited the opposite effects in both cell lines. Furthermore, ZNF148 inhibited the activity of HBV ENII/Cp and the transcriptional activity of cccDNA. Mechanistic studies revealed that ZNF148 attenuated retinoid X receptor alpha (RXRα) expression by binding to the RXRα promoter sequence. RXRα binding site mutation or RXRα overexpression abolished the suppressive effect of ZNF148 on HBV replication. The inhibitory effect of ZNF148 was also observed in the rcccDNA mouse model.ConclusionsZNF148 inhibited HBV replication by downregulating RXRα transcription. Our findings reveal that ZNF148 may be a new target for anti-HBV strategies.

Dataset Information

Evans Blue Inhibits HBV Replication Through a Dual Antiviral Mechanism by Targeting Virus Binding and Capsid Assembly.

Publications

Evans Blue Inhibits HBV Replication Through a Dual Antiviral Mechanism by Targeting Virus Binding and Capsid Assembly.

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