The roles of the pre-genomic RNA in Hepatitis B Virus nucleocapsid assembly.

前基因组 RNA 在乙型肝炎病毒核衣壳组装中的作用。

基本信息

批准号：
MR/N021517/1
负责人：
Peter Stockley
金额：
$ 43.9万
依托单位：
University of Leeds
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FN021517%2F1
关键词：
roles pre genomic RNA Hepatitis

项目摘要

Hepatitis B virus is a common infection in humans with over 2 billion people worldwide having been exposed to the virus. The majority of people recover fully from such infections but a significant minority do not, becoming carriers of the virus, a condition linked to later lethal cirrhosis and liver cancer. It is estimated that ~1 million people die every year as a result of HBV infection. In advanced western countries there is an effective vaccine, but this is not sufficient in many parts of the world where over 8% of the population may be infected carriers. As a result there is a need to devise novel anti-viral drugs that would inhibit HBV infections, and in particular render the virus visible to the immune system so that it can be cleared from patients. This is the goal of our application, which is based on a recent discovery we made relating to the way that such viruses having RNA as their genomic nucleic acid, assemble their viral particles. We have discovered that they encode a hidden instruction manual in the sequence and structure of these RNAs that ensures rapid and efficient assembly of infectious virions. HBV is a slightly unusual virus because it assembles initially around an RNA pregenomic RNA but later converts that to a double-stranded DNA version within the viral particle. In extensive preliminary experiments we have shown that HBV may well contain the same sort of instruction manual for its initial assembly. It should therefore be possible to target this process using drugs. We are asking for a two year pump-priming grant that will allow us to investigate this mechanism more comprehensively and begin to screen for the types of ligands (drugs) that could block assembly. In other viral systems, such drugs lead to partial assembly, that is they create non-infectious but highly immunogenic versions of the virus that are readily seen by the immune system. The information we gain here will be invaluable in future discussions with drug companies about developing novel anti-HBV therapy.

丙型肝炎病毒是人类的常见感染，全世界有超过20亿人暴露于该病毒。大多数人从这种感染中完全恢复过来，但很大的少数人并没有成为病毒的携带者，这种疾病与后来的致命性肝硬化和肝癌有关。据估计，由于HBV感染，每年约有100万人死亡。在先进的西方国家，有一种有效的疫苗，但这在世界许多地方还不够，那里有超过8％的人口可能被感染的承运人。结果，需要设计新型的抗病毒药物，以抑制HBV感染，尤其是使免疫系统可见病毒，以便可以从患者中清除。这是我们应用的目的，它基于我们最近发现的方法，该发现与具有RNA作为其基因组核酸的病毒的方式，组装了病毒颗粒。我们发现它们以这些RNA的顺序和结构编码隐藏的说明手册，以确保传染性病毒体的快速有效组装。 HBV是一种略有不寻常的病毒，因为它最初是在RNA前RNA围绕的，但后来将其转换为病毒颗粒中的双链DNA版本。在广泛的初步实验中，我们已经表明，HBV很可能包含同样的指令手册，以便其初始组装。因此，应该可以使用药物来靶向此过程。我们要求提供两年的泵送赠款，这将使我们能够更全面地调查该机制，并开始筛选可能阻止组装的配体（药物）的类型。在其他病毒系统中，这种药物会导致部分组装，也就是说，它们会产生非感染但高度免疫原性的病毒版本，这些病毒很容易被免疫系统看到。我们在这里获得的信息将在与制药公司关于开发新型抗HBV疗法的未来讨论中无价。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

An Intracellular Model of Hepatitis B Viral Infection: An In Silico Platform for Comparing Therapeutic Strategies.

DOI：
10.3390/v13010011
发表时间：
2020-12-23
期刊：
Viruses
影响因子：
0
作者：
Fatehi F;Bingham RJ;Dykeman EC;Patel N;Stockley PG;Twarock R
通讯作者：
Twarock R

Dysregulation of Hepatitis B Virus Nucleocapsid Assembly in vitro by RNA-binding Small Ligands.

DOI：
10.1016/j.jmb.2022.167557
发表时间：
2022-05-30
期刊：
Journal of molecular biology
影响因子：
5.6
作者：
Patel N;Abulwerdi F;Fatehi F;Manfield IW;Le Grice S;Schneekloth JS Jr;Twarock R;Stockley PG
通讯作者：
Stockley PG

RNA-Mediated Virus Assembly: Mechanisms and Consequences for Viral Evolution and Therapy.

DOI：
10.1146/annurev-biophys-052118-115611
发表时间：
2019-05-06
期刊：
Annual review of biophysics
影响因子：
12.4
作者：
Twarock R;Stockley PG
通讯作者：
Stockley PG

An age-structured model of hepatitis B viral infection highlights the potential of different therapeutic strategies.

DOI：
10.1038/s41598-021-04022-z
发表时间：
2022-01-24
期刊：
Scientific reports
影响因子：
4.6
作者：
Fatehi F;Bingham RJ;Stockley PG;Twarock R
通讯作者：
Twarock R

In vitro functional analysis of gRNA sites regulating assembly of hepatitis B virus.

DOI：
10.1038/s42003-021-02897-2
发表时间：
2021-12-16
期刊：
Communications biology
影响因子：
5.9
作者：
Patel N;Clark S;Weiß EU;Mata CP;Bohon J;Farquhar ER;Maskell DP;Ranson NA;Twarock R;Stockley PG
通讯作者：
Stockley PG