Expedited Synthesis of Glycosaminoglycans Containing Defined Sulfation Domains

含有特定硫酸化结构域的糖胺聚糖的快速合成

• 批准号: 8985640
• 负责人: Linda C Hsieh-Wilson
• 金额: $ 66.51万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8985640
• 关键词: Address; Affect; Anticoagulants; Anticoagulation; Biological; Biological Assay; Biological Process; Biology; Biomimetics; Blood coagulation; Bypass; Cell Differentiation process; Cell division; Chemicals; Chemistry; Chondroitin Sulfates; Code; Combinatorial Synthesis; Communities; Controlled Study; Development; Disaccharides; Drug Targeting; Event; Fibroblast Growth Factor; Generations; Glycosaminoglycans; Goals; Grant; Head; Heparin; Heparitin Sulfate; Inflammation; Inorganic Sulfates; Investigation; Laboratories; Libraries; Link; Mediating; Methodology; Methods; Neoplasm Metastasis; Oligosaccharides; Pattern; Pharmaceutical Preparations; Physiological; Play; Polymers; Polysaccharides; Preparation; Process; Property; Protein Binding; Protein Family; Proteins; Research; Role; Route; Specificity; Structure; Structure-Activity Relationship; Tail; Technology; Therapeutic; Time; Unspecified or Sulfate Ion Sulfates; Validation; Virus Diseases; analog; base; chondroitin sulfate glycosaminoglycan; cost effective; design; glycosylation; human disease; mimetics; neuron development; neuronal growth; novel; polymerization; public health relevance; sulfation; targeted treatment; tool

 DESCRIPTION (provided by applicant): Heparan sulfate (HS) and chondroitin sulfate (CS) glycosaminoglycans play important roles in many physiological and pathological events, such as cell division, inflammation, neuronal development, and cancer metastasis. Naturally existing HS and CS display a diverse range of sulfation patterns. While this structural diversity bestows HS and CS with the ability to interact with many proteins, it greatly hinders the ability to decipher their structure-function relationships. In order to dramatically advance an understanding of the biological functions of glycosaminoglycans, it is critical to access large, structurally diverse libraries of HS and CS oligosaccharides bearing well-defined sulfation sequences. To date, synthetic methodologies toward HS and CS are mostly target oriented, resulting in only small sets of oligosaccharides. Furthermore, it remains difficult to prepare HS and CS sequences longer than a dodecasaccharide. To address these challenges, three research groups with strong, complementary expertise in HS and CS synthesis and biology have joined forces to accomplish the following aims. In Aim 1, new synthetic strategies are proposed to accelerate the synthesis of HS oligosaccharides. Methodologies will be developed to prepare the first comprehensive library of 256 HS tetrasaccharides representing all of the possible 2-O, 6-O and N sulfation motifs, along with a library of structurally diverse 3-O sulfated tetrasaccharides and HS hexasaccharides. In Aim 2, we propose new efficient, cost-effective routes to access the first comprehensive library of CS tetrasaccharides bearing all of the possible mammalian sulfation sequences. In Aim 3, HS/CS oligosaccharide-based polymers and head-to-tail multimers will be prepared to enable access to structures containing homogeneously sulfated glycans with sizes approaching natural polysaccharides. These mimetics will possess similar domain structures and multivalent properties found in naturally existing CS and HS polysaccharides. In Aim 4, we will validate the hypothesis that our molecules can recapitulate the biological functions of HS and CS polysaccharides using well-established assays, including anticoagulation, neuronal growth, and protein-binding assays. Furthermore, we will explore the potential for these molecules to selectively target a clinically important family of proteins, the fibroblast growth factors. Together, this project will provide faster, more affordable syntheses of HS and CS, greatly expand the "chemical space" currently accessible by synthesis, enable the first direct, in-depth comparisons between HS and CS, and provide novel agents to control the activities of these biomedically important molecules.

 描述（申请人提供）：硫酸乙酰肝素（HS）和硫酸软骨素（CS）糖胺聚糖在许多生理和病理事件中发挥重要作用，例如细胞分裂、炎症、神经元发育和癌症转移。天然存在的 HS 和 CS 显示出多种硫酸化模式。虽然这种结构多样性赋予 HS 和 CS 与许多蛋白质相互作用的能力，但它极大地阻碍了破译它们的结构功能关系的能力。为了显着促进对糖胺聚糖生物学功能的理解，获取具有明确硫酸化序列的大型、结构多样的 HS 和 CS 寡糖文库至关重要。迄今为止，HS 和 CS 的合成方法大多是目标导向的，只能产生少量的寡糖。此外，制备比十二糖更长的HS和CS序列仍然很困难。为了应对这些挑战，三个在 HS 和 CS 合成及生物学领域拥有强大、互补专业知识的研究小组联手实现以下目标。在目标 1 中，提出了新的合成策略来加速 HS 寡糖的合成。将开发方法来制备第一个包含 256 种 HS 四糖的综合文库，代表所有可能的 2-O、6-O 和 N 硫酸化基序，以及结构多样的 3-O 硫酸化四糖和 HS 六糖文库。在目标 2 中，我们提出了新的高效、经济有效的途径来获取第一个包含所有可能的哺乳动物硫酸化序列的 CS 四糖综合文库。在目标 3 中，将制备基于 HS/CS 寡糖的聚合物和头尾多聚体，以获得含有均匀硫酸化聚糖且尺寸接近天然多糖的结构。这些模拟物将具有与天然存在的 CS 和 HS 多糖相似的结构域结构和多价特性。在目标 4 中，我们将验证我们的分子可以使用成熟的检测（包括抗凝、神经元生长和蛋白质结合检测）重现 HS 和 CS 多糖的生物学功能的假设。此外，我们将探索这些分子选择性靶向临床重要的蛋白质家族——成纤维细胞生长因子的潜力。总之，该项目将提供更快、更经济的 HS 和 CS 合成，极大地扩展目前可合成的“化学空间”，实现 HS 和 CS 之间的首次直接、深入比较，并提供控制这些生物医学重要分子活性的新型试剂。