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

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.

项目概要： 硫酸乙酰肝素（HS）在许多重要的生物学事件中发挥作用，包括癌症转移、抗肿瘤免疫等。 凝血和阿尔茨海默病的发展。自然界中的HS结构是异质的， 硫酸化模式和主链结构。已知HS与其生物学伴侣的相互作用是 受HS精细结构的显著影响。因此，为了彻底了解结构-活性 由于HS结构的关系，重要的是HS结构的大型库可用。然而，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 针对这一瓶颈，通过创新的行业/学术界合作，聚糖治疗将开发一种HS 如具有多样和明确分子结构的六糖库。新型六糖 模拟物将通过HS二糖的头-尾连接来设计，从而极大地简化了整体结构。 本发明涉及能够制备大量化合物用于文库合成的合成方法。 在目标1中，将开发基于溶液相的方法来合成HS样六糖 模仿天然HS。将设计稳健的接头化学以将二糖模块以头对尾的方式连接。 时尚.在目标2中，将开发用于快速合成关键二糖结构单元的方法。到 涵盖了不同的HS序列轴承2-O，6-O和N-硫酸化遇到的自然，16二糖， needed.不是从相应的单糖从头开始，而是一种新的发散性合成 将制定一项战略，其中16种二糖将来自两种关键的高级二糖 积木该方法减少了生产结构单元所需的合成步骤的总数 约50%。在目标3中，将开发自动化化学，以实现HS类的机器辅助合成 六糖模拟文库。每种化合物的结构（>98%纯度）将通过1D/2D NMR确认 和高分辨率质谱分析。所有模拟物都将在还原末端用连接体官能化， 使生物接合和微阵列生产变得容易。 在I期研究中，两种关键的策略性保护的高级二糖中间体（各500 mg）， 并将产生6种新的六糖模拟物（每种2 mg）。此外，自动化方法将 开发用于合成两种六糖样化合物（每种2 mg）。在第二阶段，合成将 放大以产生300个HS样六糖（每个2 mg）的文库。 广泛的HS六糖模拟物，将组装从这个项目将是最大的 和最全面的HS模拟库。这些产品的商业可用性将 大大加快了对HS迷人的生物学功能的理解的研究，以及 开发基于HS的新型疗法。