Medicinal chemistry strategies in the discovery and optimization of HBV core protein allosteric modulators (2018–2022 update)

Despite the improving coverage of preventative vaccines, hepatitis B remains a severe global public health problem, with more than 250 million patients living with hepatitis B virus (HBV) infection. Current available therapies, including nucleos(t)ide analogs and peginterferon, can control HBV replication but fail to eliminate covalently closed circular DNA (cccDNA) and achieve a cure. The HBV core protein (Cp) is a well-conserved structural protein, self-assembling to form the viral capsid. It involves in or modulates almost every stage of the HBV lifecycle, which makes it an attractive target for the development of new anti-HBV therapies. HBV core protein allosteric modulators (CpAMs) have become a hotspot in recent years. Herein, we provide a concise report focusing on the various medicinal chemistry strategies involved in the latest research (2018–2022) of HBV CpAMs, including high throughput screening (HTS), virtual screening (VS), drug repositioning, natural products, substitution decorating approach, scaffold hopping, molecular hybridization, prodrug strategy and conformational constraint strategy, to provide guidance for further development of new and effective anti-HBV drugs.