科学家们越来越接近乙型肝炎的药物治疗

StephenW

Public Release: 19-Jun-2017
                                    Scientists step closer to drug treatment for hepatitis B                                                

University of York

   

            
  
  
                                    A major new insight into how Hepatitis B Virus works could pave the way for new drug treatments for the infection which is the major cause of liver cancer worldwide.
        The team at the Universities of York and Leeds identified an "assembly code" in the genetic material of Hepatitis B Virus that allows it to create a protective casing in which it can produce new infectious virus particles.
        They found that the signal, generated by ribonucleic acid (RNA), helps viral proteins to overcome an 'engineering problem', assembling them into in a particular geometric pattern.
        Professor Reidun Twarock, mathematical biologist at the University of York's Department of Mathematics and Biology, said: "It is a bit like the chain on a bicycle. If we don't assemble the chain on the sprockets, it becomes tangled and won't function. Once assembled correctly, it connects the pedals with the wheels allowing the component parts to work together."
        "We see the same process happening between the Hepatitis B RNA signals and the viral proteins.  The proteins are attracted by these signals, which then promote their assembly into a precise molecular machine that allows the virus to produce a DNA copy of its genetic material and hence become infectious."
        The virus is transmitted through blood and bodily fluids. It is thought that more than two billion people have been infected worldwide, and around 350 million people remain carriers of the infection, which can, over time, result in their deaths.
        The virus occurs in Europe but is much more common in parts of Asia, especially China and Africa. There are more than one million infected people in the USA where treatments can include expensive drugs and even liver transplantation.
        Professor Peter Stockley, a structural virologist from the University of Leeds Astbury Centre, said: "There is a vaccine for the virus, but once you have the condition there is no treatment, other than drugs that can reduce symptoms but not change the long-term outlook.  
        "We often compare the disease to HIV due to the way in which the virus is passed from person-to-person, but unlike HIV there are no effective drugs to improve quality of life outcomes.  Now that we know how the virus assembles, we can interrupt the interactions with the RNA signals -- a bit like when a twig catches the sprocket on a bike, knocking the chain off."  
        The researchers are already collaborating with a team at the National Institutes of Health in the USA to identify potential drug candidates that are capable of breaking the link between RNA and proteins which should halt viral replication.

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        The research was funded by The Wellcome Trust, the Medical Research Council, and the Universities of Leeds and York, and is published in the journal Nature Microbiology.

StephenW

公开发布：2017年6月19日
科学家们越来越接近乙型肝炎的药物治疗

约克大学

乙型肝炎病毒如何运作的一个重要新见解可为新药治疗感染的方式铺平道路，这种感染是全球肝癌的主要原因。

约克和利兹大学的团队在乙型肝炎病毒的遗传物质中确定了一个“汇编代码”，允许它创建一个可以产生新的感染性病毒颗粒的保护性外壳。

他们发现由核糖核酸（RNA）产生的信号有助于病毒蛋白质克服“工程问题”，将其组装成特定的模式。

约克数学与生物学系数学生物学家Reidun Twarock教授说：“这有点像自行车上的链条，如果我们不把链条装在链轮上，就会变得纠结不了一次将踏板与轮子连接，使组件能够一起工作。

“我们看到在乙型肝炎RNA信号和病毒蛋白之间发生的相同过程，蛋白质被这些信号吸引，然后促进它们的组装成精确的分子机器，允许病毒产生其遗传物质的DNA拷贝，因此变成传染性。

病毒通过血液和血液传播。据认为，世界范围内已有超过20亿人受感染，约有3.5亿人仍然是传染媒介，随着时间的推移，这些感染可能导致其死亡。

该病毒发生在欧洲，但在亚洲部分地区尤其是中国和非洲地区更为常见。美国有一百多万感染者，治疗方法包括昂贵的药物甚至肝移植。

斯德哥尔摩教授，利兹大学阿斯特伯里中心的结构病毒学家说：“有一种疫苗用于病毒，但一旦有病情就没有治疗，除了可以减少症状但不能改变长期治疗的药物，期限展望。

“我们经常将这种疾病与艾滋病毒进行比较，因为病毒从个人到人的传播方式，但不同于艾滋病毒，没有有效的药物来改善生活质量的结果，现在我们知道病毒是如何组装的，我们可以中断与RNA信号的相互作用 - 有点像一根枝条抓住自行车上的链轮，敲开链条。

作者已经与美国国家卫生研究院的一个团队进行合作，以确定潜在的候选药物能够打破RNA和蛋白质之间的联系，从而阻止病毒复制。

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该研究由Wellcome Trust，医学研究理事会和利兹大学和约克大学资助，并发表在自然微生物学杂志上。

StephenW

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 N1, White SJ1, Thompson RF1, Bingham R2, Weiß EU2, Maskell DP1, Zlotnick A3, Dykeman EC2, Tuma R1, Twarock R2, Ranson NA1, Stockley PG1.
Author information

1
    Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.
2
    Departments of Biology and Mathematics &York Centre for Complex Systems Analysis, University of York, York YO10 5DD, UK.
3
    Department of Molecular &Cellular Biochemistry, Indiana University, Bloomington, Indiana 47405, USA.

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
DOI:
    10.1038/nmicrobiol.2017.98

StephenW

Nat微生物2017年6月19日; 2：17098。 doi：10.1038 / nmicrobiol.2017.98。
HBV RNA前基因组编码特异性基序，其介导与促进核衣壳组装的病毒核心蛋白的相互作用。
Patel N1，White SJ1，Thompson RF1，Bingham R2，WeißEU2，Maskell DP1，Zlotnick A3，Dykeman EC2，Tuma R1，Twarock R2，Ranson NA1，Stockley PG1。
作者信息

1
    Astbury利物浦大学结构分子生物学中心，利兹LS2 9JT，英国。
2
    生物与数学系纽约复合系统分析中心约克约克YO10 5DD，英国。
3
    印第安纳大学分子与细胞生物化学系，布鲁明顿，印第安纳州47405，美国。

抽象

乙型肝炎病毒核衣壳的形成是病毒生命周期中必不可少的一步，但其装配尚未完全了解。我们报告病毒前基因组与乙型肝炎核心蛋白之间的序列特异性相互作用的发现，这在确定核衣壳组装途径中发挥作用。使用RNA SELEX和生物信息学，我们在核心蛋白二聚体中以高亲和力鉴定了前基因组RNA中的多个区域。这些RNA形成具有保守循环基序的茎环，其以比不存在RNA更高的保真度和产量触发病毒样颗粒（VLP）的序列特异性装配。 RNA寡核苷酸不与预先形成的无RNA的VLP相互作用，因此它们的作用必须在粒子组装过程中发生。在其中一个RNA存在下组装的T = 4 VLP的不对称低温电子显微镜重建揭示了通过密度凸起与主要核心蛋白质壳连接的独特内部特征。生物物理测定表明，这是一个复杂的涉及几个RNA寡核苷酸与核心蛋白的C-末端富含精氨酸的结构域相互作用。这些核心蛋白质-RNA接触可能在调节核衣壳组装过程中前基因组织的组织过程中发挥一个或多个作用，促进后续的逆转录并且作为核衣壳组装的成核复合物。

结论：
    28628133
DOI：
    10.1038 / nmicrobiol.2017.98

newchinabok

好文，感谢分享

kite2002005

知道了过程，怎能杀灭，是个问题

齐欢畅2

迟早

只一个衣

感谢分享，正能量满满，期待。

hunterpt

每天都活着希望中，快十年了，继续努力

kite2002005

应该还远着