Assembling glyco-functionalized surfaces and membranes based on precision glycomacromolecules to study viral adhesion and inhibition

基于精密糖大分子组装糖功能化表面和膜来研究病毒粘附和抑制

• 批准号: 286792493
• 负责人: Professorin Dr. Laura Hartmann
• 金额: --
• 依托单位: Institut für Makromolekulare Chemie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/286792493?language=en
• 关键词: Assembling; glyco; functionalized; surfaces; membranes

Recently, we have established the solid phase synthesis of monodisperse, sequence-defined glycopolymers or so-called precision glycomacromolecules. These precision glycomacromolecules are multivalent mimics of natural oligo- and polysaccharides exhibiting high avidity and selective binding to protein receptors. We were especially interested in gaining deeper insights into the structure-property correlation of such polymeric sugar mimetics. So far, commonly used polymeric scaffolds are not well defined with regard to multivalency and sugar presentations thus hampering direct correlations between ligand structures and binding partner. Through the stepwise assembly of our precision glycomacromolecules, we obtain perfect control over the chemical structure. By controlled variations of the different structural parameters and detailed analysis of the multivalent binding of the precision glycomacromolecules to sugar-recognizing protein receptors, we have learned about the different binding modes of glycomacromolecules and how to design efficient glycomacromolecule ligands e.g. for bacteria targeting. With this approach we are able to design suitable ligands from the ground up without tedious empirical optimization as is usually done. Here, we will apply our synthetic platform for a series of glycomacromolecules targeting different viruses. Together with the Peters lab, we will synthesize glycomacromolecules presenting different mono-, di- and trisaccharide fragments of histo-blood group antigen (HBGA) epitopes and will probe the multivalent binding site of murine noroviruses (Peters and Taube labs) and human noroviruses (Hansman lab). From the Blaum lab, we will obtain di- and tetrasaccharide fragments of heparan sulfate, which will be conjugated to the macromolecular scaffolds and evaluated for their binding to Merkel cell polyomavirus MCPyV (with the Blaum lab) and human papillomavirus 16 (HPV-16) (with the Schelhaas lab). For both viral targets, the synthesis of heteromultivalent glycomacromolecules will be addressed combining the sGAG fragments with sialic acid (Sia) (for MCPyV) or non-sulfated glycosaminoglycans (GAG) fragments (for HPV), respectively. It is an intrinsic advantage of the solid phase assembly to give access to heteromultivalent glycomacromolecules. Here the simultaneous presentation of the different glycans on one polymeric backbone will be used to probe the potential cooperative binding of the glycans for viral activation.

最近，我们已经建立了单分散，顺序定义的糖共聚物或所谓的精确糖大分子的固相合成。这些精密糖大分子是天然寡糖和多糖的多价模拟物，具有高亲和力和与蛋白质受体的选择性结合。我们特别感兴趣的是深入了解这种聚合糖模拟物的结构-性能相关性。到目前为止，常用的聚合物支架在多价性和糖的表现方面还没有很好的定义，从而阻碍了配体结构和结合伙伴之间的直接关联。通过我们的精密糖大分子的逐步组装，我们获得了对化学结构的完美控制。通过控制不同结构参数的变化，详细分析糖大分子与糖识别蛋白受体的多价结合，我们了解了糖大分子的不同结合模式，以及如何设计有效的糖大分子配体，如细菌靶向。通过这种方法，我们能够从头开始设计合适的配体，而无需像通常那样进行繁琐的经验优化。在这里，我们将应用我们的合成平台，针对不同的病毒进行一系列糖大分子的合成。我们将与Peters实验室合作，合成具有不同单糖、二糖和三糖的组织-血抗原（HBGA）表位的糖大分子，并探测鼠诺如病毒（Peters和Taube实验室）和人诺如病毒（Hansman实验室）的多价结合位点。从Blaum实验室，我们将获得硫酸肝素的二糖和四糖片段，它们将被偶联到大分子支架上，并评估它们与默克尔细胞多瘤病毒MCPyV （Blaum实验室）和人乳头瘤病毒16 (HPV-16) （Schelhaas实验室）的结合。对于这两种病毒靶点，将分别将sGAG片段与唾液酸（Sia）（用于MCPyV）或非硫酸糖胺聚糖（GAG）片段（用于HPV）结合来合成异多价糖大分子。固相组装的固有优点是可以获得异多价糖大分子。在这里，不同的聚糖同时呈现在一个聚合主链上，将被用来探测聚糖潜在的协同结合，以激活病毒。