Structural Studies on Viruses, Viral Proteins and Cell Interactions

病毒、病毒蛋白和细胞相互作用的结构研究

• 批准号: MR/N00065X/1
• 负责人: David Stuart
• 金额: $ 347.75万
• 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: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN00065X%2F1
• 关键词: Structural; Studies; Viruses; Viral; Proteins

Viruses vastly outnumber cellular organisms, but reproduce inside cells, and are often very difficult to combat. Although virus diseases such as 'flu and the common cold have been with us for many years, there is always the risk of new viruses emerging as major threats to human health. The 2014 Ebola epidemic is a powerful example of such an emergent virus infection and the belief underpinning my research proposal is that a proper structural/functional understanding at the molecular and atomic level of the main lineages of viruses will provide fundamental knowledge to inform our therapeutic responses to both emerging infections and also to well known (re-emerging) virus diseases such as Hand-foot-and-mouth disease, a disease of children which is an especial problem in East Asia. Whilst disease control programmes will provide front-line defence, the fact that Smallpox and Rinderpest have been eradicated shows the power of well organised global vaccination programmes, combined with effective vaccines. Vaccines work by the recognition at the molecular level of the virus capsid and I believe that vaccine development is ready for a major revolution. The highly effective methods devised fifty years ago, based on chemical inactivation or extensive passage to deliver attenuated virus strains, might now be supplanted by the delivery of viral-like particles (VLPs) made using recombinant DNA technology so that can be highly immunogenic and yet safe. Many aspects of the requirements for such particles, for instance, correct assembly, appropriate thermal and chemical stability, can, in principle, be engineered into such particles, guided by knowledge of the atomic level structure. The other therapeutic approach to viral diseases has traditionally involved either small molecule drugs or biological agents, especially antibodies, to either prevent or treat an infection. Due to the high cost of clinical trials the delivery of such therapeutics is ultimately done by large industrial concerns and the role of academic researchers is usually limited to the pre-competitive stage. Indeed the work I propose here is primarily to develop our underpinning knowledge of the structure and function of viruses, and will mostly not in the short term lead to direct benefits to human health. However in the longer term such basic work finds applications, sometimes by opening up un-thought of therapeutic opportunities. In this broad context my programme aims to use the latest methods of structural analysis, especially electron and light microscopy and X-ray diffraction, to piece together a better understanding of how several viruses work. The major group of viruses are the picornaviruses, which include a range of human and animal pathogens, from agents of the common cold, through polio to hand-foot-and-mouth disease to hepatitis A. I will also try to illuminate the structure of the small particles of the hepatitis B vaccine and to understand how viruses such as human rotavirus (a major cause of infant death in poorer countries) function as rather complicated replicating machines. To enable this we will also develop some cutting edge methods to deliver improved analyses. Most of the viruses that I propose to work on are from virus families that include important human pathogens, however I will also explore some non-mammalian viruses, since I believe there is still untapped potential, for instance, to intervene with bacterial viruses in the fight against drug resistant bacteria.

病毒数量远远超过细胞生物，但在细胞内部繁殖，通常很难作战。尽管流感和普通感冒等病毒疾病已经存在了很多年，但总是存在新病毒作为对人类健康的主要威胁的风险。 2014年埃博拉病毒流行是这种新兴病毒感染的有力例子，而对我的研究建议的基础是，在病毒主要谱系的分子和原子水平上有适当的结构/功能理解，将提供基本知识，以提供基本知识，以使我们对新兴感染的治疗反应以及诸如众所周知的疾病（包括疾病）的疾病（ersease and and the）的疾病，以告知我们的治疗症状。东亚的特别问题。尽管疾病控制计划将提供一线防御，但已经消除了天花和浮游生物，这表明了组织良好的全球疫苗接种计划的力量，并结合了有效的疫苗。疫苗通过在病毒capsid的分子水平上识别而起作用，我认为疫苗开发已准备好进行重大革命。五十年前设计的高效方法是基于化学灭活或广泛的传递来传递衰减病毒菌株的方法，现在可以通过使用重组DNA技术制造的病毒样颗粒（VLP）来代替，因此可以高度免疫原性并且安全。例如，对此类颗粒的要求的许多方面，例如正确的组装，适当的热和化学稳定性，可以原则上设计到此类粒子中，并以对原子水平结构的了解为指导。传统上，针对病毒疾病的另一种治疗方法涉及小分子药物或生物学剂，尤其是抗体，以预防或治疗感染。由于临床试验的高成本，这种治疗剂的提供最终是由大型工业问题所做的，学术研究人员的作用通常仅限于竞争阶段。的确，我在这里提出的工作主要是为了发展我们对病毒结构和功能的基础知识，并且在短期内主要不会导致人类健康的直接利益。但是，从长远来看，此类基本工作可以找到应用程序，有时是通过开放未经思考的治疗机会。在这种广义上，我的计划旨在使用结构分析的最新方法，尤其是电子，光学显微镜和X射线衍射，以更好地了解几种病毒的工作方式。 The major group of viruses are the picornaviruses, which include a range of human and animal pathogens, from agents of the common cold, through polio to hand-foot-and-mouth disease to hepatitis A. I will also try to illuminate the structure of the small particles of the hepatitis B vaccine and to understand how viruses such as human rotavirus (a major cause of infant death in poorer countries) function as rather complicated replicating machines.为了实现这一点，我们还将开发一些最先进的方法来提供改进的分析。我建议处理的大多数病毒来自包括重要人类病原体的病毒家族，但是我还将探索一些非哺乳动物病毒，因为我认为在抗药抗药抗药物中，仍未开发的潜力，例如，干预细菌病毒。

项目成果

The human otubain2-ubiquitin structure provides insights into the cleavage specificity of poly-ubiquitin-linkages.

• DOI: 10.1371/journal.pone.0115344
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Altun M;Walter TS;Kramer HB;Herr P;Iphöfer A;Boström J;David Y;Komsany A;Ternette N;Navon A;Stuart DI;Ren J;Kessler BM
• 通讯作者: Kessler BM

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

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: 10.1101/2021.03.08.433764
• 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

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