Ligand-coated polymer for biological binding

用于生物结合的配体涂层聚合物

• 批准号: 2012492
• 金额: --
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2012492
• 关键词: Ligand; coated; polymer; biological; binding

Seasonal influenza A causes approximately 500,000 deaths and around 3-5 million cases of severe illness annually worldwide, in particular infants, elderly and more in general immunocompromised patients. On of the main hurdles in finding a long-lasting solution to this problem is the high mutation frequency of the influenza virus. This limits the use of vaccination, and vaccine must be annually readapted to circulating influenza strain mutants, with large economic costs. A similar problem arises for currently available antiviral drugs against influenza, which are becoming inactive against the latest strains. Recently, an alternative approach has been suggested, targeting conserved or inevitable viral structures which must be preserved between strain to sustain normal viral replication. In this regard, an important class of viral inhibitors under intensive study is represented by multivalent constructs displaying sialic acid receptors targeting the hemagglutinin glycoproteins of the influenza virus. In general, it is accepted that the working mechanism of this system relies in creating a competition between sialic acid receptors on the multivalent construct and similar receptors on the cell surface. The rational is that if the virus ligands are saturated by binding with these competing receptors, they cannot be used for binding to the cell surface, hence preventing viral penetration and stopping the replication cycle at its very first step. This simple picture has guided various experimental studies trying to link construct architecture and infectivity, but much has still to be understood. A central question in this regard is how the multivalent construct architecture affects the presentation of its ligand, and how this translates into a decrease in viral infectivity. To answer this question, we aim in this project to use state-of-the-art Monte Carlo simulations with coarse-grained models to provide a microscopic picture for viral inhibition by polymers. These models will provide a quantitative description of our system and we aim to translate their results into useful guidelines for the design and synthesis of novel anti-viral architectures.

季节性甲型流感每年在全球造成约 50 万人死亡和约 3-5 百万例重症病例，特别是婴儿、老年人和更多一般免疫功能低下的患者。寻找这一问题的持久解决方案的主要障碍之一是流感病毒的高突变频率。这限制了疫苗接种的使用，并且疫苗必须每年重新适应流行的流感毒株突变体，从而产生巨大的经济成本。目前可用的抗流感病毒药物也存在类似的问题，这些药物对最新毒株变得无效。最近，有人提出了一种替代方法，针对保守或不可避免的病毒结构，这些结构必须在毒株之间保留以维持正常的病毒复制。在这方面，正在深入研究的一类重要的病毒抑制剂以展示针对流感病毒的血凝素糖蛋白的唾液酸受体的多价构建体为代表。一般来说，人们普遍认为该系统的工作机制依赖于在多价构建体上的唾液酸受体与细胞表面上的类似受体之间产生竞争。其原理是，如果病毒配体通过与这些竞争性受体结合而饱和，它们就不能用于与细胞表面结合，从而阻止病毒渗透并在第一步停止复制周期。这个简单的图景指导了各种试图将构造建筑和感染力联系起来的实验研究，但还有很多东西有待理解。这方面的一个中心问题是多价构建体结构如何影响其配体的呈现，以及这如何转化为病毒感染性的降低。为了回答这个问题，我们在这个项目中的目标是使用最先进的蒙特卡罗模拟和粗粒度模型来提供聚合物抑制病毒的微观图片。这些模型将为我们的系统提供定量描述，我们的目标是将其结果转化为设计和合成新型抗病毒架构的有用指南。