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 summary

Glycosaminoglycans (GAGs) are complex carbohydrates in biology, and their biological roles and structure-function relationships are not well understood. Synthesizing large collections of structurally diverse GAG oligosaccharides would provide valuable insights and advancements in glycoscience. A new platform for synthesizing heparan sulfate (HS) oligosaccharide libraries displaying comprehensive sulfation patterns was developed, enabling the generation of a complete library of diverse HS oligosaccharides. These structures offer a unique perspective on the sulfation code of GAGs and identify sequences for modulating the activities of important growth factors and chemokines.