Investigating the role of the E5 viroporin of human papillomavirus (HPV) in transformation and the virus life cycle

研究人乳头瘤病毒 (HPV) E5 病毒孔蛋白在转化和病毒生命周期中的作用

• 批准号: MR/K012665/1
• 负责人: Andrew Macdonald
• 金额: $ 58.38万
• 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: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK012665%2F1
• 关键词: Investigating; role; E5; viroporin; human

Cervical cancer is a leading cause of death worldwide and is almost universally associated with infection with the human papillomavirus (HPV). In addition, HPV infection is also associated with an increasing number of other cancer that can affect both sexes; these include cancer of the head and neck. Not all people who are infected with HPV will develop cancer but it is thought that some of the protein building blocks produced by the virus are responsible for changing the nature of the cells that they infect so that they may eventually develop into cancerous cells. HPV expresses three of these "oncoproteins". Out of the three, the E5 protein is the least understood. This is probably due to the difficult nature of this protein that makes it hard to study.We have recently shown that E5 is able to form ring-like structures that act as a channel with a central pore that forms holes in artificial membranes that we can use to mimic the inside of cells. It is thought that this pore must allow small molecules and ions to pass through it, and perhaps this causes changes within the environment of the infected cell. We used computer based simulations of the channel to design small molecules that could block this pore and we found that these inhibitors were also able to prevent some of E5's known effects in cells.We now want to take this research further to try and understand how this channel works, what makes it open or close and can we build better inhibitors to switch it off. In addition, we want to know what the channel does in cells and whether the virus needs this channel for its life cycle. For these studies we will use cell culture experiments in the laboratory and focus on some well know effects of expressing E5 in cells.These studies should give us a clear picture of whether the E5 channel is essential for the HPV life cycle. If so then this opens up the possibility of targeting this protein for anti-viral therapeutics.

宫颈癌是世界范围内死亡的主要原因，几乎普遍与人乳头瘤病毒（HPV）感染有关。此外，HPV感染还与越来越多的其他可能影响男女的癌症有关;其中包括头部和颈部癌症。并非所有感染HPV的人都会患上癌症，但人们认为，病毒产生的一些蛋白质构建模块负责改变它们感染的细胞的性质，使它们最终可能发展成为癌细胞。HPV表达这些“癌蛋白”中的三种。在这三种蛋白中，E5蛋白是最不了解的。这可能是由于这种蛋白质的困难性质使得它很难研究。我们最近发现E5能够形成环状结构，作为一个具有中心孔的通道，在人工膜上形成孔，我们可以用它来模拟细胞内部。据认为，这个孔必须允许小分子和离子通过它，也许这会导致感染细胞环境的变化。我们使用计算机模拟通道来设计可以阻塞这个孔的小分子，我们发现这些抑制剂也能够阻止E5在细胞中的一些已知作用。我们现在想进一步研究，试图了解这个通道是如何工作的，是什么使它打开或关闭，我们可以构建更好的抑制剂来关闭它。此外，我们还想知道这个通道在细胞中的作用，以及病毒在其生命周期中是否需要这个通道。在这些研究中，我们将在实验室中使用细胞培养实验，并专注于在细胞中表达E5的一些众所周知的影响。这些研究应该给我们一个清晰的画面，E5通道是否是HPV生命周期所必需的。如果是这样的话，那么这就为靶向这种蛋白质用于抗病毒治疗开辟了可能性。

项目成果

Sortase-Modified Cholera Toxoids Show Specific Golgi Localization

分选酶修饰的霍乱类毒素显示出特定的高尔基体定位

• DOI: 10.26434/chemrxiv.9125201.v1
• 发表时间: 2019
• 作者: Machin D

Selective and potent proteomimetic inhibitors of intracellular protein-protein interactions.

• DOI: 10.1002/anie.201410810
• 发表时间: 2015-03-02
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Barnard A;Long K;Martin HL;Miles JA;Edwards TA;Tomlinson DC;Macdonald A;Wilson AJ
• 通讯作者: Wilson AJ

Agnoprotein is an Essential Egress Factor during BK Polyomavirus Infection

Agno蛋白是 BK 多瘤病毒感染期间的重要出口因子

• DOI: 10.20944/preprints201803.0001.v1
• 发表时间: 2018
• 作者: Maria-Panou M

New Structural Insights into the Genome and Minor Capsid Proteins of BK Polyomavirus using Cryo-Electron Microscopy.

• DOI: 10.1016/j.str.2016.02.008
• 发表时间: 2016-04-05
• 期刊: Structure (London, England : 1993)
• 作者: Hurdiss DL;Morgan EL;Thompson RF;Prescott EL;Panou MM;Macdonald A;Ranson NA
• 通讯作者: Ranson NA

STAT3 activation by E6 is essential for the differentiation-dependent HPV18 life cycle.

• DOI: 10.1371/journal.ppat.1006975
• 发表时间: 2018-04
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Morgan EL;Wasson CW;Hanson L;Kealy D;Pentland I;McGuire V;Scarpini C;Coleman N;Arthur JSC;Parish JL;Roberts S;Macdonald A
• 通讯作者: Macdonald A