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Cytoplasmic tail interactions of the influenza M2 protein with lipid and protein.

流感 M2 蛋白与脂质和蛋白质的细胞质尾部相互作用。

基本信息

批准号：
MR/L018578/1
负责人：
Jason Schnell
金额：
$ 49.81万
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FL018578%2F1
关键词：
Cytoplasmic tail interactions influenza M2

项目摘要

Influenza is an easily spreadable acute infection of the influenza virus that can result in severe illness and death, particularly for young children and older adults. Globally, 3-5 million people suffer severe illness and 250,000-500,000 people die from influenza every year (World Health Organization estimates). Prevention of Influenza through vaccination remains the most effective control. However, the required lead times for vaccine production and the fast evolution of circulating viruses require that development of the vaccines are based on predictions for future circulating strains. As a result, vaccine effectiveness varies widely year-to-year. Although the effectiveness rates are sometimes as high as 90%, the 2012 vaccine effectiveness was below 50%. In addition, drugs may be developed that can prevent an influenza virus infection or limit the seriousness of an infection that has occurred. Drugs that target the viral neuraminidase have been developed (oseltamivir and zanamivir). However, the efficacy of these drugs is variable and resistance to these drugs for some influenza strains is common and for others is increasing. A much older class of antivirals, the amino-adamantane (AA) drugs (rimantadine and amantadine) target the viral M2 protein and have been used for decades to treat influenza in humans and livestock. However the last decade has seen a dramatic increase in resistance to this class of drugs. The vast majority of the seasonal strains including the 2009 H1N1 "swine flu" pandemic and the 2013 H7N9 outbreak in China were resistant to the AA drugs, with swine flu M2 being particularly insensitive. However, the AA drugs, target a single activity of the M2 protein - ion channel activity. M2 is now known to possess additional activities related to the formation of new virus particles, and these activities are attributable to regions of the protein not associated with the ion channel activity. These activities include induction of host cell membrane deformation as well as specific interactions with other viral proteins that facilitate assembly of new virus particles. Our work aims to characterise these interactions at the molecular level that will enable refinement and extension of current models of the viral life cycle. These studies may ultimately pinpoint promising therapeutic approaches to treating influenza.

流感是一种容易传播的流感病毒急性感染，可导致严重疾病和死亡，特别是对幼儿和老年人。在全球范围内，每年有300 - 500万人患有严重疾病，25万-50万人死于流感（世界卫生组织估计）。通过接种疫苗预防流感仍然是最有效的控制方法。然而，疫苗生产所需的前置时间和流行病毒的快速演变要求疫苗的开发基于对未来流行毒株的预测。因此，疫苗的有效性每年都有很大差异。虽然有效率有时高达90%，但2012年的疫苗有效率低于50%。此外，可以开发可以预防流感病毒感染或限制已发生感染的严重性的药物。针对病毒神经氨酸酶的药物已经开发出来（奥司他韦和扎那米韦）。然而，这些药物的疗效是可变的，对某些流感病毒株的耐药性是常见的，而对其他流感病毒株的耐药性正在增加。一种更古老的抗病毒药物，氨基金刚烷（AA）药物（金刚乙胺和金刚烷胺）靶向病毒M2蛋白，数十年来一直用于治疗人类和牲畜的流感。然而，在过去的十年中，对这类药物的耐药性急剧增加。绝大多数季节性毒株，包括2009年H1N1“猪流感”大流行和2013年中国H7N9疫情，对AA药物具有耐药性，猪流感M2尤其不敏感。然而，AA药物靶向M2蛋白的单一活性-离子通道活性。现在已知M2具有与新病毒颗粒形成相关的额外活性，并且这些活性可归因于与离子通道活性无关的蛋白质区域。这些活性包括诱导宿主细胞膜变形以及与促进新病毒颗粒组装的其他病毒蛋白的特异性相互作用。我们的工作旨在在分子水平上研究这些相互作用，这将使目前的病毒生命周期模型得到改进和扩展。这些研究可能最终确定治疗流感的有希望的治疗方法。