Efficient platform for synthesizing comprehensive heparan sulfate oligosaccharide libraries for decoding glycosaminoglycan–protein interactions
Abstract
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.
Additional Information
© The Author(s), under exclusive licence to Springer Nature Limited 2023. Financial support was provided by the National Institutes of Health (NIH U01 GM116262 to L.C.H.-W. and X.H., R44 GM134738 to V. Pagadala, L.C.H.-W. and X.H., U01 GM116248 to N.L.B.P., and T32 GM109825 and T32 GM131994 to M.K.K.) and the National Science Foundation (DGE-1745301 to A.W.S.). We thank M. Shahgholi in the CCE Division Mass Spectrometry Facility and D. Vander Velde in the CCE Division NMR Facility at Caltech for technical support. Data availability: All data associated with this report are contained within the manuscript or the Supplementary Information. Source data are provided with this Paper. Code availability: All code associated with this report is publicly available at https://doi.org/10.5281/zenodo.7787616. Contributions: L.W., A.W.S., B.-S.H., N.P., X.H., J.L., N.L.B.P. and L.C.H.-W. designed the research. L.W., A.W.S., B.-S.H., M.K.K. and G.S. performed the research. L.W., A.W.S., B.-S.H. and L.C.H.-W. wrote the paper. Competing interests: J.L. is a founder and chief scientific officer of Glycan Therapeutics. G.S. is an employee of Glycan Therapeutics and has stock options from the company. The remaining authors declare no competing interests.Attached Files
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Additional details
- Eprint ID
- 122556
- DOI
- 10.1038/s41557-023-01248-4
- Resolver ID
- CaltechAUTHORS:20230726-216909500.20
- U01 GM116262
- NIH
- R44 GM134738
- NIH
- U01 GM116248
- NIH
- T32 GM109825
- NIH Predoctoral Fellowship
- T32 GM131994
- NIH Predoctoral Fellowship
- DGE-1745301
- NSF Graduate Research Fellowship
- Created
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2023-08-17Created from EPrint's datestamp field
- Updated
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2023-08-17Created from EPrint's last_modified field