Biophysics-Guided Lead Discovery of HBV Capsid Assembly Modifiers

Area of Science:

• Hepatology
• Virology
• Biophysics

Background:

• Hepatitis B virus (HBV) is a major global cause of chronic liver disease.
• HBV nucleocapsid assembly is a critical target for antiviral drug development.
• Capsid assembly modulators (CAMs) interfere with HBV nucleocapsid formation.

Purpose of the Study:

• To discover novel capsid assembly modulators (CAMs) for Hepatitis B virus (HBV).
• To identify compounds with moderate activity and low toxicity for HBV inhibition.
• To explore a biophysics-guided approach for drug discovery.

Main Methods:

• Utilized a combination of molecular docking and molecular dynamics simulations.
• Employed a series of biophysical assays to evaluate compound activity.
• Tested identified compounds for their effect on HBV DNA replication in vitro.

Main Results:

• Identified structurally novel CAMs with moderate antiviral activity and low toxicity.
• Observed that several compounds induce aberrant capsid formation.
• Demonstrated inhibition of HBV DNA replication in vitro by the identified compounds.

Conclusions:

• The synergistic computational and experimental approach facilitated the discovery of promising HBV CAMs.
• The identified preclinical CAMs offer opportunities for further optimization.
• These findings open new therapeutic avenues for HBV inhibition.