Homogeneous Heparan Sulfate Glycopeptides: Synthetic and Functional Studies

均质硫酸乙酰肝素糖肽：合成和功能研究

• 批准号: 9063573
• 负责人: Xuefei Huang
• 金额: $ 28.02万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9063573
• 关键词: Address; Alzheimer' s Disease; Amyloid; Binding; Biochemical Reaction; Biological; Biological Process; Blood coagulation; Cell Adhesion; Cell Death; Cell Proliferation; Cell surface; Cells; Characteristics; Chemicals; Chemistry; Clinical Trials; Complex; Dementia; Development; Enzymes; Event; Exhibits; Family; Glycopeptides; Glycosaminoglycans; Goals; Health; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Heterogeneity; Inflammation; Knowledge; Lead; Length; Ligation; Link; Malignant Neoplasms; Methodology; Methods; Nature; Neurons; Oligosaccharides; Patients; Pattern; Peptides; Play; Polysaccharides; Preparation; Property; Proteins; Proteoglycan; Reaction; Role; Route; Senile Plaques; Side; Site; Source; Specificity; Structure; Structure-Activity Relationship; Therapeutic Effect; Vertebral column; Virus Diseases; Wound Healing; base; biological systems; chemical synthesis; fascinate; flexibility; glycosylation; member; neuron development; novel; novel therapeutics; protein aminoacid sequence; screening; sulfation; syndecan 3

 DESCRIPTION (provided by applicant): Heparan sulfate proteoglycans (HSPGs) play important roles in many biological events including amyloid plaque formation, viral infection, inflammation, and cancer development. HSPGs isolated from nature exist as a highly heterogeneous mixture due to the variable structures of the heparan sulfate side chains. Heparan sulfates are traditionally believed to dictate the functions of HSPGs. Recent studies have gained increasing evidence suggesting that both the glycan chains and the core peptides/proteins can be critical. Therefore, to thoroughly understand their functions, it is important to have access to HSPGs bearing homogeneous glycans. However, to date, no general synthetic methodologies are available to prepare this type of structures. In order to overcome this obstacle, in this application, novel methodologies will be developed to synthesize these highly challenging molecules, which will then be used to understand how HSPGs interact with amyloid ß. There are four aims in this application. In aim 1, a chemical synthesis strategy will be established towards HSPG glycopeptides bearing one heparan sulfate chain. Suitable protective group and glycosylation chemistry has been developed demonstrating the feasibility of chemically synthesizing HSPG glycopeptides with one glycan chain. In aim 2, a divergent approach will be established to modify HSPG glycopeptides with heparan sulfate biosynthetic enzymes. Promising preliminary results have been obtained suggesting enzymatic synthesis can be well integrated with chemical synthesis to enable the preparation of glycopeptides with diverse glycan structures from a common intermediate. In aim 3, through a combination of chemical and enzymatic methods, HSPG glycopeptides bearing multiple glycan chains and extended peptide backbone will be produced. This will lead to glycopeptides approaching the full complexities of HSPGs. In aim 4, using the synthetic heparan sulfate/HSPG glycopeptides, the structural features critical for their interactions with amyloid ß, the pathological hallmark f Alzheimer's disease, will be identified. The proposed studies will provide the unprecedented access to HSPGs containing homogeneous heparan sulfate glycans, which will lead to exciting opportunities for studies of their fascinating biological properties.

 描述（由申请人提供）：硫酸乙酰肝素蛋白聚糖（HSPG）在许多生物学事件中发挥重要作用，包括淀粉样斑块形成、病毒感染、炎症和癌症发展。由于硫酸乙酰肝素侧链的可变结构，从自然界分离的HSPG作为高度不均匀的混合物存在。传统上认为硫酸乙酰肝素决定了HSPG的功能。最近的研究已经获得了越来越多的证据，表明聚糖链和核心肽/蛋白质都可能是关键的。因此，为了彻底了解它们的功能，重要的是要获得具有同质聚糖的HSPG。然而，迄今为止，没有通用的合成方法可用于制备这种类型的结构。为了克服这一障碍，在本申请中，将开发新的方法来合成这些具有高度挑战性的分子，然后将其用于了解HSPGs如何与淀粉样蛋白相互作用。本申请有四个目的。在目标1中，将建立一种针对具有一个硫酸乙酰肝素链的HSPG糖肽的化学合成策略。已经开发了合适的保护基和糖基化化学，证明了化学合成具有一个聚糖链的HSPG糖肽的可行性。在目标2中，将建立不同的方法来用硫酸乙酰肝素生物合成酶修饰HSPG糖肽。已经获得了有希望的初步结果，表明酶促合成可以很好地与化学合成相结合，从而能够从共同的中间体制备具有不同聚糖结构的糖肽。在目标3中，通过化学和酶促方法的组合，将产生具有多个聚糖链和延长的肽骨架的HSPG糖肽。这将导致糖肽接近HSPG的全部复杂性。在目标4中，使用合成的硫酸乙酰肝素/HSPG糖肽，将鉴定它们与淀粉样蛋白（阿尔茨海默病的病理标志）相互作用的关键结构特征。拟议的研究将提供前所未有的获得含有均匀硫酸乙酰肝素聚糖的HSPG，这将为研究其迷人的生物学特性带来令人兴奋的机会。