Khayenko Vladimir, Makbul Cihan, Schulte Clemens, Hemmelmann Naomi, Kachler Sonja, Böttcher Bettina, Maric Hans Michael
Rudolf Virchow Center, Center for Integrative and Translational Bioimaging; University of Würzburg, Würzburg, Germany.
Biocenter, University of Würzburg, Würzburg, Germany.
Elife. 2025 Mar 26;13:RP98827. doi: 10.7554/eLife.98827.
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 sub-micromolar 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.
乙型肝炎病毒（HBV）感染是一个重大的全球健康问题，慢性感染会导致肝脏并发症并造成高死亡率。目前的治疗方法，如核苷（酸）类似物和α干扰素，能有效抑制病毒复制，但很少能治愈感染。为了解决这一问题，正在研发针对HBV分子机制不同组成部分的新型抗病毒药物。在此，我们研究了形成病毒衣壳并在HBV生命周期中起关键作用的乙型肝炎核心蛋白（HBc）。我们探索了HBV衣壳上两个不同的结合口袋：HBc二聚体的中央疏水口袋和衣壳尖峰处的口袋。我们合成了一种以微摩尔亲和力与中央口袋结合的香叶基二聚体，以及以亚微摩尔亲和力与尖峰末端口袋结合的二聚体肽。冷冻电子显微镜进一步证实了肽二聚体与衣壳尖峰末端的结合及其衣壳聚集特性。最后，我们表明肽二聚体在体外和活细胞中诱导HBc聚集。我们的研究结果突出了HBV衣壳内两个易于处理的位点，并提供了一种影响HBV衣壳的替代策略。
