Synthesis of the library of heparan sulfate hexasaccharide mimetics

硫酸乙酰肝素六糖模拟物文库的合成

• 批准号: 10759528
• 负责人: Guowei Su
• 金额: $ 25.5万
• 依托单位: GLYCAN THERAPEUTICS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2024-03-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10759528
• 关键词: Academia; Acceleration; Alzheimer' s Disease; Anticoagulation; Automation; Biological; Biological Process; Chemicals; Chemistry; Collaborations; Communities; Consumption; Development; Disaccharides; Event; Generations; Goals; Grant; Head; Heparitin Sulfate; Heterogeneity; High Pressure Liquid Chromatography; Immobilization; Industry; Length; Libraries; Link; Location; Mass Spectrum Analysis; Methodology; Methods; Microarray Analysis; Molecular Structure; Monosaccharides; Nature; Neoplasm Metastasis; Nuclear Magnetic Resonance; Oligosaccharides; Pattern; Phase; Play; Polysaccharides; Preparation; Procedures; Process; Production; Property; Publishing; Reaction; Research; Resolution; Role; Services; Solid; Structure; Structure-Activity Relationship; Sulfate; Tail; Therapeutic; Time; Vertebral column; commercialization; design; fascinate; glycosylation; human disease; innovation; member; mimetics; new technology; novel; novel therapeutics; phase 1 study; scale up; tool; Academia; Acceleration; Alzheimer' s Disease; Anticoagulation; Automation; Biological; Biological Process; Chemicals; Chemistry; Collaborations; Communities; Consumption; Development; Disaccharides; Event; Generations; Goals; Grant; Head; Heparitin Sulfate; Heterogeneity; High Pressure Liquid Chromatography; Immobilization; Industry; Length; Libraries; Link; Location; Mass Spectrum Analysis; Methodology; Methods; Microarray Analysis; Molecular Structure; Monosaccharides; Nature; Neoplasm Metastasis; Nuclear Magnetic Resonance; Oligosaccharides; Pattern; Phase; Play; Polysaccharides; Preparation; Procedures; Process; Production; Property; Publishing; Reaction; Research; Resolution; Role; Services; Solid; Structure; Structure-Activity Relationship; Sulfate; Tail; Therapeutic; Time; Vertebral column; commercialization; design; fascinate; glycosylation; human disease; innovation; member; mimetics; new technology; novel; novel therapeutics; phase 1 study; scale up; tool

Project summary: Heparan sulfate (HS) play roles in many important biological events, including cancer metastasis, anti- coagulation, and Alzheimer’s disease development. HS structures in nature are heterogeneous with a wide range sulfation patterns and backbone structures. The interactions of HS with their biological partners are known to be significantly impacted by the fine structures of HS. Thus, for a thorough understanding of the structure-activity relationships of HS, it is critical that large libraries of HS structures are available. However, synthesis of HS oligosaccharide libraries remains a tremendous challenge due to the complexity of HS structures. To overcome this bottleneck, through an innovative industry/academia collaboration, Glycan Therapeutics will develop a HS like hexasaccharide library with diverse and well-defined molecular structures. The novel hexasaccharide mimetics will be designed through head-to-tail linkage of HS disaccharides, thus greatly simplifying the overall synthetic process enabling the preparation of a large number of compounds for library synthesis. In aim 1, solution phase based methodologies will be developed to synthesize HS like hexasaccharides mimicking native HS. Robust linker chemistry will be designed to link the disaccharide modules in a head-to-tail fashion. In aim 2, methods will be developed for expedient synthesis of the key disaccharide building blocks. To cover the diverse HS sequences bearing 2-O, 6-O and N-sulfation encountered in nature, 16 disaccharides are needed. Rather than starting from the corresponding monosaccharides de novo, a new divergent synthetic strategy will be developed where the 16 disaccharides will be derived from two key advanced disaccharide building blocks. This process reduces the total number of synthetic steps needed to produce the building blocks by ~50%. In aim 3, automation chemistry will be developed to enable machine aided synthesis of the HS like hexasaccharide mimetic library. The structure of each compound (>98% purity) will be confirmed by 1D/2D NMR and high-resolution mass spectrometry. All mimetics will be functionalized with a linker at the reducing end to enable facile bioconjugation and microarray production. In Phase I studies, two key strategically protected advanced disaccharide intermediates (500 mg each), and 6 new hexasaccharide mimetics (2 mg each) will be produced. In addition, automated method will be developed to synthesize two hexasaccharide like compounds (2 mg each). In Phase II, the synthesis will be scaled up to produce a library of 300 HS like hexasaccharides (2 mg each). The extensive HS hexasaccharide mimetics that will be assembled from this project will be the largest and the most comprehensive HS mimic library available. The commercial availability of these products would greatly accelerate research on the understanding of the fascinating biological functions of HS, as well as the development of novel HS-based therapeutics.

项目摘要： 硫酸肝素（HS）在许多重要的生物学事件中起着作用，包括癌症转移，抗 凝血和阿尔茨海默氏病的发展。自然界中的HS结构是异质的，范围很广 硫酸模式和骨干结构。 HS与其生物伴侣的相互作用已知 受HS的精细结构的显着影响。为了彻底理解结构活动 HS的关系，至关重要的是可以使用大量HS结构的库。但是，HS的合成 由于HS结构的复杂性，寡糖文库仍然是一个巨大的挑战。克服 通过创新的行业/学术界合作，这种瓶颈将开发HS 就像具有多样化且定义明确的分子结构的六糖文库一样。新颖的六糖 Mimetics将通过HS二糖的头到尾链接设计，因此非常简化整体 合成过程，可以制备大量化合物用于库合成。 在AIM 1中，将开发基于溶液阶段的方法来合成HS等HS（例如六糖） 模仿本地HS。强大的接头化学将旨在将二糖模块从头到尾连接起来 时尚。在AIM 2中，将开发方法来方便地合成关键的二糖构建块。到 覆盖携带2-O，6-O和N-硫化的潜水员HS序列，在自然界中遇到16个二糖 需要。而不是从相应的单糖从头开始，而是一种新的发散合成 将制定策略，其中16种二糖将来自两个关键的高级二糖 构建块。此过程减少了产生构建块所需的合成步骤的总数 约50％。在AIM 3中，将开发自动化化学以启用机器帮助HS的合成 六糖模拟图书馆。每种化合物的结构（纯度> 98％）将通过1D/2D NMR确认 和高分辨率质谱。所有模拟物将在还原端的连接器中官能化 启用便捷的生物缀合和微阵列生产。 在第一阶段的研究中，两个关键在战略性保护的晚期二糖中间体（每个500毫克）， 将产生6种新的六糖Mimetics（每种2毫克）。此外，自动化方法将是 开发以合成两种类似化合物（每种2 mg）的六糖。在第二阶段，合成将是 缩放以产生300 hs的库，例如六糖（每个2毫克）。 从该项目组装的大量HS六糖Mimetics将是最大的 以及最全面的HS模拟库。这些产品的商业可用性将 大大加速了对HS的迷人生物学功能的理解的研究 开发基于HS的新型治疗。