Exploiting Vulnerability on Influenza Virus

利用流感病毒的漏洞

基本信息

批准号：
9526599
负责人：
IAN A WILSON
金额：
$ 73.02万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9526599
关键词：
Animals Antibodies Antiviral Agents Anxiety Appearance Binding Binding Sites Biochemical Biological Assay Biology Biophysics Birds Carbohydrates Chemicals China Collaborations Collection Complex Computer-Assisted Image Analysis Crystallization Development Drug Design Drug Targeting Economic Burden Epidemic Epitopes Evolution Exhibits Explosion Fc Receptor Foundations Future Goals H7N7 Head Hemagglutinin Human Hydrophobicity Immune system Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H5N1 Subtype Influenza A Virus, H7N9 Subtype Influenza A virus Influenza B Virus Influenza Hemagglutinin Libraries Mediating Membrane Fusion Membrane Glycoproteins Mutation Names Neuraminidase Non-Prescription Drugs Parents Peptides Pharmaceutical Preparations Population Protein Engineering Protein Fragment Proteins Resolution Russia Serotyping Site Specificity Structure Surface Surface Antigens Vaccine Design Viral Virus Virus Diseases Yeasts Zoonoses analog anti-influenza base combat combinatorial design discount drug discovery fitness flu health economics improved influenzavirus inhibitor/antagonist insight iterative design mimicry neutralizing antibody novel novel therapeutics pandemic disease pandemic influenza prevent receptor receptor binding response seasonal influenza small molecule small molecule inhibitor stem structural biology therapeutic candidate

项目摘要

PROJECT SUMMARY / ABSTRACT 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 of HA and NA in avian and other animal reservoirs have been associated with human pandemics (H1N1, H2N2, H3N2). However, ever increasing anxiety about pandemic threats stemming from influenza viruses of zoonotic origins have heightened concern about emergence of a human transmissible virus that could devastate the human population. The recent appearance of H5N1, H6N1, H7N7, H7N9, H9N2, and H10N8 viruses in the human population are constant reminders of this possibility. Influenza B viruses with their two distinct lineages further increase the health and economic burden of seasonal influenza worldwide. In this proposal, we aim to elucidate, at the structural level, key sites of vulnerability on influenza virus and incorporate the essential information on how antibodies and receptor analogs target these sites into structure- based design, development, and synthesis of novel therapeutics. Antibody-mediated neutralization of influenza virus is a complex combinatorial problem for the human immune system when 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 and provided us with valuable new insights into conserved sites of vulnerability. We are 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 entry of influenza virus. As a proof-of-concept of our approach, we have determined the crystal structure of umifenovir (an antiviral for influenza infection used in Russia and China) in complex with HA and exploited this structural information to synthesize a derivative with 100x improved binding. We will elucidate common features for recognition of these sites of vulnerability in pandemic and emerging influenza viruses from crystal structures of diverse HAs with broadly neutralizing antibodies as well as sialosides that are mimics of the natural receptor. A combined biophysical, biochemical, and chemical approach employing state-of-the- art structural biology, yeast-display evolution, and chemical biology will be harnessed to design and synthesize small molecules as novel therapeutic candidates to control and combat the threat of future influenza pandemics as well as seasonal epidemics.

项目摘要 /摘要流感病毒表现出极端多样性，例如血清谷蛋白的多种血清型（HA，HA， H1-H18）和神经氨酸酶（Na，N1-N11）表面抗原。迄今为止，可能只有三个 HA和NA在Avian和其他动物水库中的组合与人类大流行有关（H1N1，H2N2，H3N2）。但是，对流感引起的大流行威胁的焦虑越来越大人畜共患病毒的病毒对人类可传染病毒的出现的关注加剧了可能破坏人口。 H5N1，H6N1，H7N7，H7N9，H9N2和人口中的H10N8病毒是对这种可能性的不断提醒。流感B病毒与他们两个独特的血统进一步增加了全球季节性流感的健康和经济负担。在这个提案，我们旨在在结构层面上阐明流感病毒和结合有关抗体和受体类似物如何将这些位点靶向结构的基本信息 - 新型治疗学的基于设计，开发和合成。抗体介导的流感中和病毒是人类免疫系统的复杂组合问题，当可变且不断发展的病毒。传统上，对人类流感中和抗体是中和抗体被认为是特定于应变的，最近的进步表明，可以安装更广泛的响应并为我们提供了对保守脆弱场所的宝贵新见解。我们正在积累引人注目的证据表明可以对流感和这种重要的持续跨色谱反应安装现在可以利用信息来设计小分子，肽和蛋白质以靶向这些键脆弱性的部位，从而阻止了流感感染。目前没有有效的药物可用于防止流感病毒进入。作为我们方法的概念证明，我们已经确定了晶体 Umifenovir的结构（俄罗斯和中国使用的流感感染抗病毒）与HA和HA和利用这些结构信息以合成具有100倍改进结合的衍生物。我们将阐明识别这些大流行和新兴流感病毒中这些脆弱性部位的共同特征从不同的晶体结构具有广泛中和的抗体以及模仿的唾液剂天然受体。采用最新的生物物理，生化和化学方法合并艺术结构生物学，酵母 - 戏剧演化和化学生物学将被利用以设计和合成小分子作为新的治疗候选者，以控制和应对未来流感的威胁大流行以及季节性流行病。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Recurring and Adaptable Binding Motifs in Broadly Neutralizing Antibodies to Influenza Virus Are Encoded on the D3-9 Segment of the Ig Gene.

DOI：
10.1016/j.chom.2018.09.010
发表时间：
2018-10-10
期刊：
Cell host & microbe
影响因子：
30.3
作者：
Wu NC;Yamayoshi S;Ito M;Uraki R;Kawaoka Y;Wilson IA
通讯作者：
Wilson IA

Clinical Correlations of Transcriptional Profile in Patients Infected With Avian Influenza H7N9 Virus.

DOI：
10.1093/infdis/jiy317
发表时间：
2018-09-08
期刊：
The Journal of infectious diseases
影响因子：
0
作者：
Guan W;Yang Z;Wu NC;Lee HHY;Li Y;Jiang W;Shen L;Wu DC;Chen R;Zhong N;Wilson IA;Peiris M;Mok CKP
通讯作者：
Mok CKP

Structural insights into the design of novel anti-influenza therapies.