Abstract
Approximately 257 million people chronically infected with hepatitis B virus (HBV) worldwide are at risk of developing hepatocellular carcinoma (HCC). However, despite the availability of potent nucleoside/tide inhibitors, currently there are no curative therapies for chronic HBV infections. To identify potential new antiviral molecules, a select group of compounds previously evaluated in clinical studies were tested against 12 different viruses. Amongst the compounds tested, SRI-32007 (CYT997) demonstrated antiviral activity against HBV (genotype D) in HepG2.2.2.15 cell-based virus yield assay with 50% effective concentration (EC50) and selectivity index (SI) of 60.1 nM and 7.2, respectively. Anti-HBV activity of SRI-32007 was further confirmed against HBV genotype B in huh7 cells with secreted HBe antigen endpoint (EC50 40 nM and SI 250). To determine the stage of HBV life cycle inhibited by SRI-32007, time of addition experiment was conducted in HepG2-NTCP cell-based HBV infectious assay. Results indicated that SRI-32007 retained anti-HBV activity even when added 72 hours postinfection (72 h). Additional mechanism of action studies demonstrated potent inhibition of HBV core promoter activity by SRI-32007 with an EC50 of 40 nM and SI of >250. This study demonstrates anti-HBV activity of a repurposed compound SRI-32007 through inhibition of HBV core promoter activity. Further evaluation of SRI-32007 in HBV animal models is needed to confirm its activity in vivo. Our experiments illustrate the utility of repurposing strategy to identify novel antiviral chemical leads. HBV core promoter inhibitors such as SRI-32007 might enable the development of novel therapeutic strategies to combat HBV infections.
Highlights
Worldwide approximately 257 million people are chronically infected with hepatitis B virus (HBV) (Global Hepatitis Report, 2017 World Health Organization)
HBV virions uncoat in the cytoplasm, and the viral nucleocapsids are transported into the nucleus, where a mixture of host and viral enzymes convert the partially double-stranded viral relaxed circular DNA into covalently closed circular DNA. cccDNA is crucial for formation of subgenomic RNA and pregenomic RNA. sgRNA produces the polymerase (P) protein, which gets packaged into the viral nucleocapsid along with the pgRNA
We describe here the antiviral activity of SRI32007 against HBV using virus yield assay, secreted HBe antigen (Ag), infectious virus assay, and further demonstrate that SRI-32007 exerts its anti-HBV activity through inhibition of HBV core promoter
Summary
Worldwide approximately 257 million people are chronically infected with hepatitis B virus (HBV) (Global Hepatitis Report, 2017 World Health Organization). HBV virions uncoat in the cytoplasm, and the viral nucleocapsids are transported into the nucleus, where a mixture of host and viral enzymes convert the partially double-stranded viral relaxed circular DNA (rcDNA) into covalently closed circular DNA (cccDNA). SgRNA produces the polymerase (P) protein, which gets packaged into the viral nucleocapsid along with the pgRNA. Nucleocapsids contribute to either virus formation/maturation or cccDNA amplification. In the virus formation pathway, a portion of the nucleocapsids containing the rcDNA matures via the endoplasmic reticulum (ER) and gets excreted through the cellular protein secretion pathways as Advances in Virology “infectious viral particles.”. In the cccDNA amplification pathway, nucleocapsids recycle back into the nucleus to amplify cccDNA and produce more sgRNA and pgRNA In the virus formation pathway, a portion of the nucleocapsids containing the rcDNA matures via the endoplasmic reticulum (ER) and gets excreted through the cellular protein secretion pathways as Advances in Virology “infectious viral particles.” In the cccDNA amplification pathway, nucleocapsids recycle back into the nucleus to amplify cccDNA and produce more sgRNA and pgRNA
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