新发现有望推动乙肝药物开发
近日，一个英国科研人员主导的团队日前在英国期刊《自然·微生物学》发表报告说，他们发现了乙型肝炎病毒产生作用的关键机制，这一成果有助医学界未来开发出治疗这一疾病的有效药物。乙肝是由乙型肝炎病毒造成的可能威胁生命的肝脏感染，可造成慢性感染，患者死于肝硬化和肝癌的风险很高。虽然人们可以通过接种乙肝疫苗进行预防，但目前还没有治疗乙肝的药物。
由英国利兹大学和约克大学研究人员领衔的团队深入分析了乙肝病毒。他们发现，这种病毒的遗传物质中存在一种“组合代码”，能够让病毒形成一个保护层，从而在其中复制出新的具感染性病毒分子。进一步分析显示，乙肝病毒核糖核酸产生的信号能吸引病毒蛋白，还能使病毒蛋白按一种特定的几何型态进行组合。
据研究人员介绍，这一机制好比自行车的链条，如果链条没有被拼接到链轮上就会缠在一起，无法发挥正常作用，但如果正确地组合在一起，就能把脚踏板与车轮联动起来，自行车才能正常运行。
报告作者之一、利兹大学教授彼得·斯托克利说，弄清病毒如何组合后，我们就能尝试去阻断核糖核酸信号与病毒蛋白的互动，让病毒无法顺利复制。
目前团队已开始与美国同行合作，以便找到破坏这一机制的候选药物，未来或许能形成一个成熟的治疗方案。
Nat Microbiol. 2017 Jun 19;2:17098. doi: 10.1038/nmicrobiol.2017.98.
HBV RNA pre-genome encodes specific motifs that mediate interactions with the viral core protein that promote nucleocapsid assembly.
Patel N#1, White SJ#1, Thompson RF1, Bingham R2, Weiß EU2, Maskell DP1, Zlotnick A3, Dykeman E2, Tuma R1, Twarock R2, Ranson NA1, Stockley PG1.
Author information
Abstract
Formation of the hepatitis B virus nucleocapsid is an essential step in the viral lifecycle, but its assembly is not fully understood. We report the discovery of sequence-specific interactions between the viral pre-genome and the hepatitis B core protein that play roles in defining the nucleocapsid assembly pathway. Using RNA SELEX and bioinformatics, we identified multiple regions in the pre-genomic RNA with high affinity for core protein dimers. These RNAs form stem-loops with a conserved loop motif that trigger sequence-specific assembly of virus-like particles (VLPs) at much higher fidelity and yield than in the absence of RNA. The RNA oligos do not interact with preformed RNA-free VLPs, so their effects must occur during particle assembly. Asymmetric cryo-electron microscopy reconstruction of the T = 4 VLPs assembled in the presence of one of the RNAs reveals a unique internal feature connected to the main core protein shell via lobes of density. Biophysical assays suggest that this is a complex involving several RNA oligos interacting with the C-terminal arginine-rich domains of core protein. These core protein-RNA contacts may play one or more roles in regulating the organization of the pre-genome during nucleocapsid assembly, facilitating subsequent reverse transcription and acting as a nucleation complex for nucleocapsid assembly.
PMID: 28628133 PMCID: PMC5495169 DOI: 10.1038/nmicrobiol.2017.98 https://www.nature.com/articles/nmicrobiol201798
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