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) 在许多重要的生物事件中发挥作用，包括癌症转移、抗 凝血和阿尔茨海默病的发展。自然界中的 HS 结构是异质的，范围广泛 硫酸化模式和主链结构。已知 HS 与其生物伙伴的相互作用是 HS的精细结构影响显着。因此，为了全面了解结构-活性 由于 HS 关系，拥有大型 HS 结构库至关重要。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，通过创新的工业界/学术界合作，Glycan Therapeutics 将开发一种 HS 像具有多样且明确的分子结构的六糖库。新型六糖 模拟物将通过HS二糖的头尾连接来设计，从而大大简化了整体 合成过程能够制备大量用于库合成的化合物。 在目标 1 中，将开发基于溶液相的方法来合成 HS 类六糖 模仿原生 HS。强大的连接化学将被设计为以头尾相连的方式连接二糖模块 时尚。在目标 2 中，将开发关键二糖结构单元的便捷合成方法。到 涵盖了自然界中遇到的带有 2-O、6-O 和 N-硫酸化的不同 HS 序列，共 16 种二糖 需要。不是从头开始相应的单糖，而是一种新的不同的合成物 将制定战略，其中 16 种二糖将从两种关键的先进二糖中衍生出来 积木。该过程减少了生产构件所需的合成步骤总数 约 50%。在目标 3 中，将开发自动化化学，以实现 HS 的机器辅助合成，例如 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端通过连接子进行功能化 实现轻松的生物共轭和微阵列生产。 在第一阶段研究中，两种关键的战略性保护的高级二糖中间体（每种 500 毫克）， 将生产 6 种新的六糖模拟物（每种 2 毫克）。此外，自动化方法将 开发用于合成两种六糖类化合物（每种 2 毫克）。在第二阶段，合成将是 扩大规模以产生 300 个 HS 类六糖（每个 2 毫克）的文库。 该项目将组装的广泛 HS 六糖模拟物将是最大的 以及最全面的 HS 模拟库。这些产品的商业可用性将 极大地加速了对 HS 迷人生物学功能以及 开发基于 HS 的新型疗法。