Chemo-enzymatic synthesis of nucleotide sugar libraries and therapy-relevant derivatives

Glycans and glycoconjugates are widespread in nature and play pivotal roles in cell cell recognitioncell differentiationand immunological responsesMost glycans and glycosylation reactions require nucleotide sugars as their essential building blocksThereforethe commercial availability of nucleotide sugars will determine future opportunities for carbohydrate based innovationsjust as the availability of nucleotides was a prerequisite for today s $billion PCR market of DNA based technologiesDue to glycoscience s reliance on nucleotide sugarsthere is an urgent need for a production pipeline to provide these essential reagentsThe goal of ourChemo enzymatic synthesis of nucleotide sugar libraries and therapy relevant derivativesFast Track project is to meet this need and commercialize a stableaffordable and diverse supply of nucleotide sugars to drive advances in glycoscienceIt is our long term objective to bringnucleotide sugarsnucleotide derivativesand the associated processes to marketIn Phase I Aimwe will enzymatically synthesize GDP L FucGDP ManCMP Neu AcCMP Neu GcandUDP sugarsGlcGalGlcNAcGalNAcGlcAGalAand XylIn Aimwe will create optimized in situ generation systems for the UDPGDPand CMP sugars to be coupled with transferase reactionsOur methods will utilize de novo or salvage pathway enzymes and be scaled up togram production reactionsIn Phase II Aimwe will chemically modify the nucleotide sugars to formnew derivatives containing azidofluoridedeoxy or methoxy functional groups at various positions on CMP Neu AcGDP L Fucand UDP GlcNAc GalNAcIn Aimwe will further optimize allproduction platforms for commercializationOur methods will combine chemical synthesis with de novo and salvage pathway enzyme reactions to produce the most efficient productsThe health relevance of this project is linked to developments in glycan technologydue the fundamental nature of nucleotide sugars as building blocks for glycoconjugates and polysaccharidesA stable supply of nucleotide sugars and their derivatives will facilitate experiments that advance our understanding of cell surface markerscell recognitionand protein carbohydrate interactionsIn turnthis cell specific information has the potential to impact individualized medicinedrug deliveryand cell targeting therapies