SYNTHESIS, CONFORMATION AND APPLICATION OF GLYCOPEPTIDES

人工合成的多肽可用于研究血管紧张素转换酶的作用。 翻译修饰广泛的生化， 前两个循环中的生物物理和生物过程 格兰特，我们已经为固相研究开发了新方法 糖肽类化合物的合成及主要作用的确立 糖基化对构象、体外稳定性和 多肽骨架的某些生物识别特性。 然而，我们和其他人到目前为止提供的例子是 在大小和复杂性上有限。 在目前的建议中，我们将进行以下研究 糖肽在更复杂的系统中。我们将准备并使用 合成抗菌糖肽，到目前为止还没有 提供有用的数量，以充分描述其范围 活动和行动方式。病理生物化学过程是 由于潜在的N-糖基化可能存在异常 蛋白质的糖基化位点也将用 与人类tau蛋白片段相对应的糖肽， 神经原纤维缠结的主要蛋白质成分 阿尔茨海默病~S病。不同糖基化版本的 粘蛋白蛋白的重复单位将作为 糖长依赖的糖蛋白片段 单抗和T细胞的识别将是 特色化的。为此，N-末端保护的麦芽三糖-和 麦芽七糖偶联的丝氨酸和苏氨酸残基 用化学方法准备的。这些衍生品也将被用作 中、长糖辅助剂的积木 细胞表位多肽模型研究细胞表位多肽结合 糖肽对主要组织相容性蛋白(MHC)的作用 T细胞受体。最后，一种可能的生物技术用途 糖肽将使用甘露糖化的T细胞表位进行评估， 其中糖的附属物有望帮助传递 抗原提呈细胞内隔室的表位 细胞。 上述研究将辅之以对 待处理糖肽的二级结构和稳定性 关于行动方式和期限的具体问题，以及 糖链长度和异构体构型相关 构象转变。这笔赠款的模式和方法 建议可以在以后作为原型用于研究较新的一组 糖肽/糖蛋白的功能，并可能打开新的大门 集成开发环境和应用。

Synthetic peptides can be used to investigate the effect of post- translational modifications on a wide range of biochemical, biophysical and biological processes In the first tow cycles of this grant, we have developed new methodologies for the solid-phase synthesis of glycopeptides and have established the principle effects glycosylation exerts on the conformational, in vitro stability and certain biological recognition properties of the peptide backbone. However, the examples provided by us and others to date are limited in size and complexity. In the current proposal, we will undertake the study of glycopeptides in more complex systems. We will prepare and use synthetic antibacterial glycopeptides, which have hitherto not been available in useful quantities to fully characterize their range of activity and mode of action. Pathobiochemical processes that are due to possible abnormal hyperglycosylation of potential N- glycosylation sites of proteins will also be studies with glycopeptides corresponding to fragments of the human tau protein, the main proteinaceous component of the neurofibrillary tangles of Alzheimer~s disease. Differentially glycosylated versions of the repeat unit of the mucin protein will serve as models of glycoprotein fragments on which the sugar length-dependent recognition of monoclonal antibodies and T-cells will be characterized. To this end, N-terminally protected, maltotriose-and maltoheptose-coupled serine and threonine residues will be chemically prepared. These derivatives will also be used as building blocks for middle-sized and long sugar containing T helper cell epitopic peptide models to study the binding of the glycopeptides to major histocompatibility proteins (MHC) and the T-cell receptor. Finally, a possible biotechnological use of glycopeptides will be assessed using mannosylated T-cell epitopes, in which the sugar appendages are expected to help deliver the epitopes to the intracellular compartments of antigen presenting cells. The above listed studies will be complemented with analysis of the secondary structure and stability of the glycopeptides to address specific questions concerning the mode and duration of action, and the sugar length-and anomeric configuration-dependent conformational transitions. The models and methods of this grant proposal can be used later as prototypes for studying a newer set of glycopeptide/glycoprotein functions, and may open doors to new ides and applications.