Diverse Heparan Sulfate Oligosaccharide Libraries For Understanding and Therapeutically Manipulating Glycosaminoglycans

Heparan sulfateHSis a highly sulfated polysaccharide with important roles in many physiological and pathological eventsThe structural diversity of naturally existing HSwhich exhibits diverse sulfation patternshas hindered the understanding of its structure activity relationshipsTo datesynthetic methodologies toward HS are mostly target orientedleading to a small set of oligosaccharidesTo enable a deeper understanding of HS biologythe availability of large collections of HS oligosaccharides is criticalGlycan Therapeutics is a company specialized in HS related research productsIn this projectGlycan Therapeutics will collaborate with leading experts in HS synthesis to produce and commercialize large libraries of HS oligosaccharidesIn Aimthe synthesis of key disaccharide building blocks will be expeditedRather than starting from monosaccharidesnew methods have been developed to hydrolyze natural heparin and heparosan polysaccharides to obtain disaccharidesThese disaccharides can then be transformed into suitably protected building blocks ready for glycosylation and glycan chain extensionNotablythis process reduces the total number of synthetic steps needed to produce the disaccharide building blocks byIn Aima comprehensive library of HS tetrasaccharides bearing all possibleOO and N sulfation sequences will be synthesizedA new protective group strategy has been designed that will enableHS tetrasaccharides to be accessed from only four strategically protected tetrasaccharides by automated solidphase synthesisAll tetrasaccharides are functionalized to facilitate bioconjugation and microarray studiesIn Aima library ofC labeled oligosaccharide standards carrying aUAunsaturated residue at the nonreducing end will be synthesizedA common method for researchers to determine HS composition is to use heparin lyases to degrade HS into disaccharidesfollowed by disaccharide composition analysis using LC MSCurrentlythere are no commercial sources for stable isotopically labeledO sulfated standardsGlycan Therapeutics will synthesize a series of these standards to enable quantitative analysis of HS compositionIn Phase I studiesfour key strategically protected disaccharidesmg eachfour protected strategically protected tetrasaccharide precursorsmg eachten fully deprotectedsulfated HS tetrasaccharidesmg eachas well as twoC labeled andO sulfated HS oligosaccharidesmg eachwill be preparedIn Phase II studiesthe synthesis will be scaled up to produce the strategically protected disaccharidesg eachthemember library of HS tetrasaccharides bearing all possibleOO and N sulfation sequencesmg eachand aC labeled andO HS oligosaccharide librarycompoundsmg eachThe new HS structures that will become available from this project will represent the largestmost comprehensive HS libraries to dateSuccessful commercialization of these products will greatly accelerate research on the chemistry and biology of HSand facilitate the development of HS based therapeutics Project Narrative Heparan sulfate is a biomedically important polysaccharideThe overall goals of this project are to synthesize and commercialize large collections of heparan sulfate oligosaccharidesThis will provide novel agents to expedite an in depth understanding of their exciting biology and therapeutic potential