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: 9221340
• 负责人: Xuefei Huang
• 金额: $ 27.89万
• 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/9221340
• 关键词: Address; Alzheimer' s Disease; Amyloid beta-Protein; 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; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Heterogeneity; Inflammation; Knowledge; Length; Ligation; Link; Malignant Neoplasms; Methodology; Methods; Nature; Neurons; Oligosaccharides; Pathologic; Patients; Pattern; Peptides; Play; Polysaccharides; Preparation; Property; Proteins; Proteoglycan; Reaction; Role; Route; Senile Plaques; Side; Site; Source; Specificity; Structure; Structure-Activity Relationship; Therapeutic Effect; Unspecified or Sulfate Ion Sulfates; Vertebral column; Virus Diseases; Wound Healing; base; biological systems; chemical synthesis; fascinate; flexibility; glycosylation; member; neuron development; novel; novel therapeutics; protein aminoacid sequence; public health relevance; 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）在许多生物事件中发挥重要作用，包括淀粉样蛋白斑形成、病毒感染、炎症和癌症发展。由于硫酸乙酰肝素侧链的结构可变，从自然界分离的 HSPG 作为高度异质混合物存在。传统上认为硫酸乙酰肝素决定 HSPG 的功能。最近的研究获得了越来越多的证据表明聚糖链和核心肽/蛋白质都至关重要。因此，为了彻底了解它们的功能，获得带有均质聚糖的 HSPG 非常重要。然而，迄今为止，还没有通用的合成方法可用于制备此类结构。为了克服这一障碍，在本应用中，将开发新的方法来合成这些极具挑战性的分子，然后将其用于了解 HSPG 如何与淀粉样蛋白 ß 相互作用。该应用程序有四个目标。在目标 1 中，将建立一种针对带有硫酸乙酰肝素链的 HSPG 糖肽的化学合成策略。已经开发出合适的保护基团和糖基化化学，证明化学合成具有一条聚糖链的 HSPG 糖肽的可行性。在目标 2 中，将建立一种不同的方法，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，表明酶合成可以与化学合成很好地结合，从而能够从常见的中间体制备具有不同聚糖结构的糖肽。在目标3中，通过化学和酶法的结合，将生产带有多个聚糖链和延伸肽主链的HSPG糖肽。这将导致糖肽接近 HSPG 的全部复杂性。在目标 4 中，将使用合成的硫酸乙酰肝素/HSPG 糖肽，鉴定其与淀粉样蛋白（阿尔茨海默病的病理标志）相互作用的关键结构特征。拟议的研究将为含有均质硫酸乙酰肝素聚糖的 HSPG 提供前所未有的途径，这将为研究其迷人的生物学特性带来令人兴奋的机会。