The content explores two distinct binding pockets on the hepatitis B virus (HBV) core protein (HBc) as potential targets for developing new antivirals.
The first pocket is a hydrophobic pocket located at the center of HBc dimers. The authors synthesized a geranyl dimer that binds to this pocket with micromolar affinity. Cryo-electron microscopy confirmed the binding of geraniol to this pocket.
The second pocket is located at the tips of the capsid spikes. The authors designed dimeric peptides that bind to this pocket with nanomolar affinity, significantly higher than their monomeric counterparts. These peptide dimers were found to induce aggregation of HBc in vitro and in living cells expressing HBc.
The authors provide structural insights into the binding of these dimeric compounds to the HBc capsid. They demonstrate that the peptide dimers can cross-link neighboring HBc dimers or capsids, leading to aggregation. This aggregation effect resembles the capsid assembly modulation observed with classical HBc-targeting antivirals.
The findings highlight the potential of targeting these alternative binding pockets on the HBc as a strategy to disrupt the HBV life cycle, complementing existing approaches that target the canonical hydrophobic pocket at the HBc dimer-dimer interface.
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by Khay... klo www.biorxiv.org 05-01-2024
https://www.biorxiv.org/content/10.1101/2024.04.29.591677v1Syvällisempiä Kysymyksiä