Exploiting sites of vulnerability on influenza viruses

 描述(由申请人提供)：甲型流感病毒表现出极端的多样性，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就是例证。到目前为止，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种与人类大流行有关(H1N1、H2N2、H3N2)。然而，人们对人畜共患传染病感染可能性的担忧与日俱增，加剧了人们对出现一种人类传播病毒的担忧，这种病毒可能会摧毁人类人口。人类群体中出现的H5N1、H6N1、H7N7、H7N9、H9N2和H10N8病毒不断提醒人们这种可能性。B型流感病毒具有两种不同的谱系，进一步增加了全球季节性流感的健康和经济负担。这项提议试图在结构层面上阐明流感病毒易受攻击的关键部位，这些部位可被用来开发治疗方法和改进疫苗。抗体介导的流感病毒中和对于人类免疫系统来说是一个复杂的组合问题，因为它呈现出多样化、高度可变和不断进化的病毒。虽然针对人类流感的中和抗体传统上被认为是毒株特异性的，但最近的进展表明，可以进行更广泛的反应，从而对保守的脆弱部位提供有价值的见解。因此，我们正在收集令人信服的证据，表明可以对流感进行持续的跨血清型反应，现在可以利用这些重要信息来设计小分子、多肽和蛋白质，以针对这些关键的脆弱部位，从而阻止流感感染。目前还没有预防流感病毒进入的有效药物。因此，我们将阐明从具有广泛中和抗体和唾液酸苷的不同晶体结构中识别大流行和新出现的流感病毒易患部位的共同特征，这些抗体和唾液酸苷是天然受体的模拟物。将使用一种综合的生物物理、生化和化学方法，使用最先进的结构生物学、多糖阵列和化学生物学来提供对流感病毒中和的关键见解，从而能够设计新的疗法来控制和抗击未来的流感大流行和季节性流行病。

 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.