Exploiting sites of vulnerability on influenza viruses

利用流感病毒的脆弱点

• 批准号: 9114253
• 负责人: IAN A WILSON
• 金额: $ 83.59万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9114253
• 关键词: Animals; Antibodies; Antigens; Anxiety; Attention; Binding; Binding Sites; Biochemical; Biology; Birds; Calorimetry; Cells; Chemicals; Collaborations; Collection; Communities; Complex; Computer-Assisted Image Analysis; Crystallography; Development; Differential Scanning Calorimetry; Economic Burden; Electron Microscopy; Epidemic; Epithelial Cells; Epitopes; Exhibits; Explosion; Future; Germ Lines; Goals; H7N7; Head; Health; Hemagglutinin; Human; Human Virus; Immune response; Immune system; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H7N9 Subtype; Influenza A virus; Influenza B Virus; Influenza Hemagglutinin; Interferometry; Intervention; Knowledge; Maps; Mediating; Membrane Glycoproteins; Molecular; Mutation; Neuraminidase; Peptides; Pharmaceutical Preparations; Polysaccharides; Population; Proteins; Resolution; Serotyping; Site; Specificity; Structure; Surface; Surface Antigens; Therapeutic; Titrations; Vaccine Design; Vaccine Therapy; Vaccines; Viral; Virus; Virus Diseases; Virus Receptors; Zoonotic Infection; base; biophysical techniques; combat; combinatorial; design; fitness; flu; health economics; improved; influenza virus vaccine; influenzavirus; inhibitor/antagonist; insight; knowledge base; mimicry; neutralizing antibody; novel; novel therapeutics; pandemic disease; pandemic influenza; prevent; receptor; receptor binding; response; seasonal influenza; sialic acid receptor; small molecule; stem; structural biology; vaccinology

 DESCRIPTION (provided by applicant): Influenza A viruses exhibit extreme diversity as exemplified by the multiple serotypes of the hemagglutinin (HA, H1-H18) and neuraminidase (NA, N1-N11) surface antigens. To date, only three of the possible 198 combinations found in avian and other animal reservoirs have been associated with human pandemics (H1N1, H2N2, H3N2). However, ever increasing anxiety about the potential for infections by infections of zoonotic origin have heightened concern about emergence of a human transmissible virus that could devastate the human population. The emergence of H5N1, H6N1, H7N7, H7N9, H9N2, and H10N8 viruses in the human population are constant reminders of this possibility. Influenza B viruses with its two distinct lineages further increase the health and economic burden of seasonal influenza worldwide. This proposal seeks to elucidate, at the structural level, key sites of vulnerability on influenza virus that can be utilized to develop therapeutics as well as improved vaccines. Antibody-mediated neutralization of influenza virus is a complex combinatorial problem for the human immune system as it is presented with diverse, highly variable and constantly evolving viruses. While neutralizing antibodies against human flu are traditionally regarded as being strain specific, recent advances have shown that much broader responses can be mounted that give valuable insights into conserved sites of vulnerability. We are therefore amassing compelling evidence that a sustained, cross- serotype response can be mounted against influenza and this vital information can now be harnessed for design of small molecules, peptides, and proteins to target these key sites of vulnerability, thereby blocking influenza infection. No effective drugs are currently available for preventing the entry of influenza virus. Thus, we will elucidate common features for recognition of sites of vulnerability of pandemic and emerging influenza viruses from crystal structures of diverse HAs with broadly neutralizing antibodies and sialosides that are mimics of the natural receptor. A combined biophysical, biochemical, and chemical approach employing state- of-the-art structural biology, glycan arrays, and chemical biology will be used to provide key insights into influenza virus neutralization that enable design of novel therapeutics to control and combat future influenza pandemics and seasonal epidemics.

 性状（由申请方提供）：甲型流感病毒表现出极大的多样性，如血凝素（HA，H1-H18）和神经氨酸酶（NA，N1-N11）表面抗原的多种血清型所示。迄今为止，在禽类和其他动物宿主中发现的198种可能的组合中，只有3种与人类大流行病有关（H1N1、H2 N2、H3 N2）。然而，对人畜共患病来源的感染的潜在感染的日益增加的焦虑已经增加了对可能使人类种群死亡的人传播病毒的出现的关注。H5 N1、H6 N1、H7 N7、H7N9、H9 N2和H10 N8病毒在人群中的出现不断提醒人们这种可能性。具有两个不同谱系的B型流感病毒进一步增加了全球季节性流感的健康和经济负担。该提案试图在结构水平上阐明流感病毒的关键脆弱性位点，这些位点可用于开发治疗方法以及改进的疫苗。抗体介导的流感病毒中和是人类免疫系统的一个复杂的组合问题，因为它存在多种多样、高度可变和不断进化的病毒。虽然抗人类流感的中和抗体传统上被认为是菌株特异性的，但最近的进展表明，可以建立更广泛的反应，从而对保守的脆弱性位点提供有价值的见解。因此，我们正在收集令人信服的证据，证明可以针对流感建立持续的跨血清型应答，并且现在可以利用这些重要信息来设计小分子、肽和蛋白质，以靶向这些关键的脆弱部位，从而阻断流感感染。目前还没有有效的药物来防止流感病毒的进入。因此，我们将阐明共同的特点，从晶体结构的不同HA与广泛中和抗体和唾液酸是模拟的天然受体的大流行和新出现的流感病毒的脆弱性的网站识别。采用最先进的结构生物学、聚糖阵列和化学生物学的组合生物物理、生物化学和化学方法将用于提供对流感病毒中和的关键见解，从而能够设计新的治疗方法来控制和对抗未来的流感大流行和季节性流行病。

项目成果

A Perspective on the Structural and Functional Constraints for Immune Evasion: Insights from Influenza Virus.

关于免疫逃避的结构和功能约束的观点：来自流感病毒的见解。

• DOI: 10.1016/j.jmb.2017.06.015
• 发表时间: 2017-08-18
• 期刊: Journal of molecular biology
• 影响因子: 5.6
• 作者: Wu NC;Wilson IA
• 通讯作者: Wilson IA

In vitro evolution of an influenza broadly neutralizing antibody is modulated by hemagglutinin receptor specificity.

• DOI: 10.1038/ncomms15371
• 发表时间: 2017-05-15
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Wu NC;Grande G;Turner HL;Ward AB;Xie J;Lerner RA;Wilson IA
• 通讯作者: Wilson IA

Structure and Dynamics of Stacking Interactions in an Antibody Binding Site.

抗体结合位点中堆积相互作用的结构和动力学。

• DOI: 10.1021/acs.biochem.9b00119
• 发表时间: 2019
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Adhikary,Ramkrishna;Zimmermann,Jörg;Stanfield,RobynL;Wilson,IanA;Yu,Wayne;Oda,Masayuki;Romesberg,FloydE
• 通讯作者: Romesberg,FloydE