Efficient platform for synthesizing comprehensive heparan sulfate oligosaccharide libraries for decoding glycosaminoglycan-protein interactions.

Glycosaminoglycans (GAGs) are abundant, ubiquitous carbohydrates in biology, yet their structural complexity has limited an understanding of their biological roles and structure-function relationships. Synthetic access to large collections of well defined, structurally diverse GAG oligosaccharides would provide critical insights into this important class of biomolecules and represent a major advance in glycoscience. Here we report a new platform for synthesizing large heparan sulfate (HS) oligosaccharide libraries displaying comprehensive arrays of sulfation patterns. Library synthesis is made possible by improving the overall synthetic efficiency through universal building blocks derived from natural heparin and a traceless fluorous tagging method for rapid purification with minimal manual manipulation. Using this approach, we generated a complete library of 64 HS oligosaccharides displaying all possible 2-O-, 6-O- and N-sulfation sequences in the tetrasaccharide GlcN-IdoA-GlcN-IdoA. These diverse structures provide an unprecedented view into the sulfation code of GAGs and identify sequences for modulating the activities of important growth factors and chemokines.

Automated Solution-Phase Synthesis of S-Glycosides for the Production of Oligomannopyranoside Derivatives.

Thioglycosides are more resistant to enzymatic hydrolysis than their O-linked counterparts, thereby becoming attractive targets for carbohydrate-based therapeutic development. We report the first development of methods for the site-selective incorporation of S-linkages into automated solution-phase oligosaccharide protocols. The protocols were shown to be compatible with the formation of S- or O-glycosides for the synthesis of mannopyranoside trimmers that incorporate both S- and O-linkages to allow the selective incorporation of an S-glycoside in various stages in an automated program.