
Synthetic dimeric compounds targeting two distinct binding pockets on the hepatitis B virus core protein can induce capsid aggregation, providing an alternative strategy to disrupt the viral life cycle.


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The hepatitis B virus (HBV) infection is a major global health problem, with chronic infection leading to liver complications and high death toll. Current treatments, such as nucleos(t)ide analogs and interferon-α, effectively suppress viral replication but rarely cure the infection. To address this, new antivirals targeting different components of the HBV molecular machinery are being developed. Here we investigated the hepatitis B core protein (HBc) that forms the viral capsids and plays a vital role in the HBV life cycle. We explored two distinct binding pockets on the HBV capsid: the central hydrophobic pocket of HBc-dimers and the pocket at the tips of capsid spikes. We synthesized a geranyl dimer that binds to the central pocket with micromolar affinity, and dimeric peptides that bind the spike-tip pocket with nanomolar affinity. Cryo-electron microscopy further confirmed the binding of peptide dimers to the capsid spike tips and their capsid-aggregating properties. Finally, we show that the peptide dimers induce HBc aggregation in vitro and in living cells. Our findings highlight two tractable sites within the HBV capsid and provide an alternative strategy to affect HBV capsids.

### Competing Interest Statement

The authors have declared no competing interest.

Induction of Hepatitis B Core Protein Aggregation Targeting an Unconventional Binding Site

targeting-unconventional-binding-sites-on-the-hepatitis-b-virus-core-protein-to-induce-capsid-aggregation


Targeting Unconventional Binding Sites on the Hepatitis B Virus Core Protein to Induce Capsid Aggregation
