Structural studies of viruses and their interactions with cells

病毒的结构研究及其与细胞的相互作用

• 批准号: MR/V001329/1
• 负责人: David Stuart
• 金额: $ 311.73万
• 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: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV001329%2F1
• 关键词: Structural; studies; viruses; their; interactions

Viral diseases have been responsible for massively damaging pandemics in the past, the best known example being the influenza outbreak of 1918. In recent years we have mercifully escaped such global disasters, however there is still a real and present risk. Thus the September 2019 report of the WHO Global Preparedness Monitoring Board (https://apps.who.int/gpmb/assets/annual_report/GPMB_annualreport_2019.pdf) warned that "there is a very real threat of a rapidly moving, highly lethal pandemic of a respiratory pathogen killing 50 to 80 million people and wiping out nearly 5% of the world's economy". One of their required actions is "ensure adequate investment in development of innovative vaccine and therapeutics, surge manufacturing capacity, broad-spectrum antivirals and appropriate non-pharmaceutical interventions". The programme proposed here does not primarily address lethal respiratory viruses, however it does address two important families of viral pathogens, the Picornaviridae and the Reoviridae. Picornaviruses are responsible not only for a very large proportion of respiratory tract infections, but also for other major epidemics, notably several million cases per year of hand-foot-and-mouth disease. Although one of the best known picornavirus diseases, polio, is almost eliminated there has been a concerning increase in cases recently (https://www.who.int/news-room/detail/07-01-2020-statement-o-the-twenty-third-ihr-emergency-committee-regarding-the-international-spread-of-poliovirus) and there are still serious cases of acute flaccid paralysis due to another enteroviruses. Frequent recombination events occurring between two co-infecting picornaviruses will no doubt lead to the emergence and re-emergence of numerous picornavirus caused diseases. Similarly, amongst the Reoviridae rotaviruses are estimated to cause several hundred million cases of gastroenteritis every year. Thus the viruses we propose to target represent significant global health burdens, but there are still a rather small number of vaccines available and no licenced anti-picornavirus drugs. There is a clear unmet need for novel therapeutics. Due to the continuing revolution in cryo-electron imaging it is now a golden age for structural virology and yet there remain major gaps in our understanding of how they work. The idea driving the current programme is that integrated structural biology is now sufficiently powerful that it can provide a wealth of atomic level information to feed into the search for new therapies, but can also contribute to the broader cellular level understanding of the full complexity of the virus life cycle. The goal of this programme is to make genuine contributions to answering some fundamental questions, and to at least set a direction of travel towards improved treatment.

过去，病毒疾病一直是巨大破坏大流行病的原因，最著名的例子是1918年的流感爆发。近年来，我们仁慈地逃脱了这样的全球灾难，但是仍然存在现实和当前的风险。因此，2019年9月的全球准备委员会（https://apps.who.int/gpmb/assets/annual_report/gpmb_annualreport_2019.pdf）的报告警告说：“存在着一个非常真实的威胁，对杀害50亿人的经济状况的快速移动，高度致命的病原体杀害了50亿人的呼吸势力很高，这是一个非常真实的人，几乎是50亿人的经济困难。他们所需的行动之一是“确保在开发创新疫苗和治疗学，激增的制造能力，广谱抗病毒药和适当的非药物干预措施方面进行足够的投资”。此处提出的该计划并未主要解决致命的呼吸道病毒，但是它确实针对了两个重要的病毒病原体家庭，Picornaviridae和reoviridae。 PICORNAVIRES不仅对很大一部分的呼吸道感染负有责任，而且还负责其他主要流行病，尤其是每年的手脚疾病几百万例。 Although one of the best known picornavirus diseases, polio, is almost eliminated there has been a concerning increase in cases recently (https://www.who.int/news-room/detail/07-01-2020-statement-o-the-twenty-third-ihr-emergency-committee-regarding-the-international-spread-of-poliovirus) and there are still serious cases of另一个肠病毒引起的急性松弛瘫痪。在两个共同感染的Picornaviruse之间发生的频繁重组事件无疑会导致许多Picornavirus的出现和重新出现引起疾病。同样，据估计，依维氏病毒的轮状病毒每年会引起数亿例胃肠炎病例。因此，我们建议靶向的病毒代表着巨大的全球健康负担，但仍有少数可用的疫苗，没有许可的抗皮科尔诺病毒药物。对新型治疗学有明显的未满足的需求。由于冷冻电子成像的持续革命，现在是结构性病毒学的黄金时代，但我们对它们的工作方式的理解仍然存在重大差距。驱动当前程序的想法是，整合结构生物学现在已经足够强大，可以提供大量的原子水平信息以供人们寻找新疗法，但也可以有助于更广泛的细胞水平理解病毒生命周期的全部复杂性。该计划的目的是为回答一些基本问题做出真正的贡献，并至少为改善治疗方向设定了旅行方向。

项目成果

A conserved glutathione binding site in poliovirus is a target for antivirals and vaccine stabilisation.

• DOI: 10.1038/s42003-022-04252-5
• 发表时间: 2022-11-25
• 期刊: Communications biology
• 影响因子: 5.9

Site-specific steric control of SARS-CoV-2 spike glycosylation

• DOI: 10.1101/2021.03.08.433764
• 发表时间: 2021-03
• 期刊: bioRxiv
• 作者: Joel D. Allen;H. Chawla;Firdaus Samsudin;Lorena Zuzic;A. T. Shivgan;Yasunori Watanabe;Wan-ting He;Sean Callaghan;G. Song;Peter Yong;P. Brouwer;Yutong Song;Yongfei Cai;Helen M. E. Duyvesteyn;T. Malinauskas;J. Kint;P. Pino;Maria J. Wurm;M. Frank;Bing Chen;D. Stuart;R. Sanders;R. Andrabi;D. Burton;Sai Li;P. Bond;M. Crispin

A conserved glutathione binding site in poliovirus is a target for antivirals and vaccine stabilisation

• DOI: 10.1101/2022.09.08.507136
• 发表时间: 2022-09-08
• 期刊: bioRxiv
• 作者: Bahar, M. W.;Nasta, V.;Stuart, D. I.
• 通讯作者: Stuart, D. I.

Site-Specific Steric Control of SARS-CoV-2 Spike Glycosylation.

• DOI: 10.1021/acs.biochem.1c00279
• 发表时间: 2021-07-13
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Allen JD;Chawla H;Samsudin F;Zuzic L;Shivgan AT;Watanabe Y;He WT;Callaghan S;Song G;Yong P;Brouwer PJM;Song Y;Cai Y;Duyvesteyn HME;Malinauskas T;Kint J;Pino P;Wurm MJ;Frank M;Chen B;Stuart DI;Sanders RW;Andrabi R;Burton DR;Li S;Bond PJ;Crispin M
• 通讯作者: Crispin M

Publisher Correction: A conserved glutathione binding site in poliovirus is a target for antivirals and vaccine stabilisation.

• DOI: 10.1038/s42003-022-04378-6
• 发表时间: 2022-12-23
• 期刊: Communications biology
• 影响因子: 5.9