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

最近，我们已经建立了单分散，序列定义的糖共聚物或所谓的精确糖大分子的固相合成。这些精确的糖大分子是天然寡糖和多糖的多价模拟物，表现出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-性质相关性。到目前为止，常用的聚合物支架没有很好地定义关于多价性和糖介绍，从而阻碍配体结构和结合伴侣之间的直接相关性。通过逐步组装我们的精密糖大分子，我们可以完美控制化学结构。通过不同结构参数的受控变化和精确糖大分子与糖识别蛋白受体的多价结合的详细分析，我们已经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，例如用于细菌靶向。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，我们将把我们的合成平台应用于一系列靶向不同病毒的糖大分子。与Peters实验室一起，我们将合成呈现组织血型抗原（HBGA）表位的不同单糖，二糖和三糖片段的糖大分子，并将探测鼠诺如病毒（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，我们将获得硫酸乙酰肝素的二糖和四糖片段，将其与大分子支架结合，并评价其与默克尔细胞多瘤病毒MCPyV（与Blaum实验室）和人乳头瘤病毒16（HPV-16）（与Schelhaas实验室）的结合。对于这两种病毒靶标，将分别将sGAG片段与唾液酸（Sia）（对于MCPyV）或非硫酸化糖胺聚糖（GAG）片段（对于HPV）组合来解决异多价糖大分子的合成。固相组装的固有优点是可以获得异多价的糖大分子。在此，不同聚糖在一个聚合物主链上的同时呈现将用于探测用于病毒活化的聚糖的潜在协同结合。

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.