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

• 批准号: 8985156
• 负责人: NICOLA L. B. POHL
• 金额: $ 59.23万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8985156
• 关键词: Alkylation; Automation; Biological Process; Carbohydrates; Chemicals; Chemistry; Collection; Controlled Environment; Disease; Ensure; Fucose; Funding Mechanisms; Galactosamine; Galactose; Glucosamine; Glucose; Goals; Hand; Health; Heating; Human; Human Milk; Lead; Lectin; Libraries; Lipopolysaccharides; Mannose; Manuals; Mass Spectrum Analysis; Metals; Methods; Monosaccharides; N-Acetylneuraminic Acid; Oligosaccharides; Phase; Plant Resins; Polysaccharides; Preparation; Procedures; Production; Proteins; Protocols documentation; Pseudomonas aeruginosa; Reaction; Reagent; Relative (related person); Rhamnose; Route; S Phase; Site; Solid; Solutions; Strontium; Structure; Surface; Technology; Therapeutic; base; carbohydrate structure; catalyst; design; interest; pathogen; public health relevance; response; scale up; sugar

 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.