Structure-based Design of Novel Hepatitis B Virus Capsid Assembly Modulators

Area of Science:

• Medicinal Chemistry
• Virology
• Drug Discovery

Background:

• Chronic hepatitis B virus (HBV) infection remains a significant global health challenge.
• Small-molecule capsid assembly modulators (CAMs) are emerging as a novel therapeutic strategy against HBV.
• Developing effective and safe antiviral agents for HBV is a priority.

Purpose of the Study:

• To discover novel small-molecule HBV capsid assembly modulators (CAMs).
• To identify potent lead compounds through in silico screening and subsequent optimization.
• To evaluate the antiviral potential and mechanism of action of novel HBV CAM candidates.

Main Methods:

• Target-based in silico screening was employed to identify initial HBV CAM hits.
• Focused library synthesis and chemical optimization were performed on weakly active compounds.
• In vitro potency, physico-chemical properties, molecular docking, and mechanism of action studies were conducted.

Main Results:

• Initial screening identified several weakly active compounds.
• Optimization led to the discovery of lead compound 42 and analogues 56 and 57.
• These compounds demonstrated sub- and micromolar in vitro potency with favorable physico-chemical properties.

Conclusions:

• Novel small-molecule HBV CAMs were successfully identified and optimized.
• Lead compounds exhibit promising antiviral potential for treating chronic HBV infection.
• Further investigation into these compounds could lead to new therapeutic options for hepatitis B.