Identification of Compounds Targeting Hepatitis B Virus Core Protein Dimerization through a Split Luciferase...

Area of Science:

• Virology
• Drug Discovery
• Molecular Biology

Background:

• The hepatitis B virus (HBV) capsid is a key target for antiviral therapies against chronic infection.
• Existing therapies (CpAMs) primarily target interactions between HBV core protein dimers, not monomers.
• Screening for compounds affecting monomer interactions is limited by a lack of suitable models.

Purpose of the Study:

• To develop and validate a cell-based assay for screening compounds that modulate HBV core protein dimerization.
• To identify novel regulators of HBV capsid assembly by targeting monomer-monomer interactions.
• To evaluate the antiviral activity of identified compounds against HBV DNA replication.

Main Methods:

• Development of a split luciferase complementation (SLC) assay to monitor HBV core protein dimer formation in cells.
• Screening of a library containing 672 compounds using the SLC assay.
• In vitro assessment of identified compounds for their effects on HBV DNA replication and capsid formation.

Main Results:

• A novel cell-based assay utilizing SLC was established to detect HBV core dimer formation.
• Two compounds, Arbidol (umifenovir) and 20-deoxyingenol, were identified as regulators of core dimerization from 672 screened compounds.
• Arbidol and 20-deoxyingenol demonstrated inhibition of HBV DNA replication in vitro, with distinct effects on core dimer and capsid formation.

Conclusions:

• The developed cell-based SLC assay provides a proof-of-concept for screening agents targeting HBV core dimer and capsid formation.
• Arbidol and 20-deoxyingenol represent potential lead compounds for developing new anti-HBV therapies.
• Targeting the initial steps of HBV capsid assembly, specifically monomer dimerization, is a viable strategy for antiviral drug development.