Sugar Building Blocks and Automated Synthesis of Biomedically-Relevant Glycans

糖构建模块和生物医学相关聚糖的自动合成

基本信息

批准号：
9513573
负责人：
NICOLA L. B. POHL
金额：
$ 51.9万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2022-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The overall goals of this project, in response to RFA-RM-14-015 titled "Facile Methods and Technologies for Synthesis of Biomedically Relevant Carbohydrates (U01)" are (I) to pioneer more efficient chemical methods to access a core set of differentially protected carbohydrate building blocks-currently a major bottleneck in the chemical construction of oligosaccharides, (II) to achieve readily reproducible, automated solution-phase synthetic methods to connect these building blocks into glycans and (III) to establish automated purification protocols and analysis methods to ensure purity of final products. Because automated protocols require greater specification of variables than manual procedures, such protocols should aid in the facile adaptation of these methods between automated and manual syntheses to set up standard operating procedures for the synthesis of a set of key glycans implicated in human health and disease. To achieve these objectives, five specific aims will be pursued: 1) to optimize methods to simplify the synthesis of carbohydrate building blocks by a metal-catalyzed derivatization of monosaccharides; 2) to develop synthetic routes using the above methods to rhamnose-based sugar building blocks that will result in automated reproducible methods to synthesize oligorhamnose compounds associated with the lipopolysaccharide core of the human pathogen Pseudomonas aeruginosa; 3) to develop synthetic routes using the above and other methods to galactose, fucose, and glucosamine building blocks that will enable reproducible parallel automated solution-phase methods to synthesize small libraries of human milk oligosaccharides; 4) to develop synthetic routes using the above and other methods to make glucosamine and mannose building blocks that will lead to reproducible parallel automated solution-phase methods to synthesize human protein-associated higher mannose-type N-glycan structures currently unavailable in publicly available microarray collections; and 5) to develop synthetic routes to make additional building blocks to then afford reproducible parallel automated solution-phase methods to synthesize human protein-associated O-glycan structures needed for mass spectrometry standards and related structures that are also currently unavailable in microarray collections.

DESCRIPTION (provided by applicable): The overall goals of this project, in response to RFA-RM-14-015 titled "Facile Methods and Technology for Synthesis of Biomedically Relevant Carbohydrates (U01)" are (I) to pioneer more efficient chemical methods to access a core set of differently protected carbonhydrate building blocks-currently a major bottleneck in the chemical construction of oligosaccharides, (II) to achieve容易重现的，自动化的溶液相合成方法，将这些构建块连接到聚糖和（iii）以建立自动纯化协议和分析方法以确保最终产品的纯度。由于自动化协议需要比手动程序更大的变量规范，因此此类协议应有助于在自动化和手动合成之间便利适应这些方法，以建立标准操作程序，以综合人类健康和疾病中实施的一组关键的大乳腺。为了实现这些目标，将实现五个具体目标：1）优化方法，通过金属催化的单糖衍生化来简化碳氢化物的合成； 2）使用上述方法开发合成途径，用于基于鼠李糖的糖构建块，这将导致自动可重复的方法合成与人类病原体假单胞菌的脂多糖核心相关的寡头型化合物； 3）使用上述方法和其他方法开发合成途径，用于半乳酸，岩藻糖和葡萄糖胺的组成部分，这些块将使可重复的平行自动化溶液相方法综合人乳寡糖的小文库； 4）使用上述方法和其他方法开发合成路线，以制造葡萄糖和甘露糖的构件，从而导致可重现的平行自动化溶液相方法，以合成人类蛋白质相关的高甘露糖型N-Glycan结构，目前在公开可用的微阵列集合中目前无法使用； 5）要开发合成途径以制造额外的构建块，然后负担得起的平行自动化溶液相方法，以合成质谱标准和相关结构所需的人蛋白质相关的O-聚糖结构，这些结构目前在微阵列集合中也不可用。