Decoding heparan sulfate structure and function

Heparan sulfate glycosaminoglycans (HS GAGs) are a family of linear, sulfated polysaccharides that decorate the surface of cells in all animals. This conserved class of glycans mediate many biological processes such as cell differentiation, pathogen adherence, infection and immunity, cancer metastasis and blood coagulation. Given their roles in such a diverse array of processes, HS GAGs have tremendous therapeutic potential, both as targets of therapeutic intervention and as drugs themselves. However, much of this potential remains untapped due to their incredible structural complexity, which arises from the distinct sulfation and acetylation sequences that are implemented along the length of the glycan.​ Thus, a central focus of our lab is to develop methods and platforms to characterize and exploit structure-function relationships of HS GAGs

Structurally defined HS tetrasaccharide library
Recently, we developed new expedited and automated platforms for synthesizing heparan sulfate (HS) oligosaccharide libraries that display comprehensive arrays of sulfation patterns. Library synthesis is made possible via disaccharide synthons derived from natural heparin, which significantly reduces the number of steps. From these synthons, a universal building block is then elaborated via a divergent synthetic strategy into 64 different sulfation motifs. Notably,a traceless fluorous tagging method enables rapid purification of the highly charged intermediates and can be used with solution-phase automation. Using this approach, we generated the first comprehensive library of 64 HS tetrasaccharides displaying all possible 2-O-, 6-O-, and N-sulfation sequences.
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Pawar et al., "Expedient Synthesis of Core Disaccharide Building Blocks from Natural Polysaccharides for Heparan Sulfate Oligosaccharide Assembly” Angewandte Chemie International Edition 2019 
DOI: https://doi.org/10.1002/anie.201908805
Wang et al., “Efficient Platform for Synthesizing Comprehensive Heparan Sulfate Oligosaccharide Libraries for Decoding Glycosaminoglycan-Protein Interactions” Nature Chemistry 2023
DOI: https://doi.org/10.1038/s41557-023-01248-4

Molecular Recognition of HS Glycans
Structurally-enriched and structurally-defined HS glycans provide powerful insights into the interactions between HS and protein ligands. We use defined oligosaccharides in a suite of biochemical and biophysical assays to characterize HS-ligand interactions. With our recent developments in comprehensive library synthesis, we are able to systemically assess the contributions of fine-structural features of HS oligosaccharides to ligand binding. We foresee these studies as a powerful avenue for understanding the functions encoded in specific HS sulfation sequences.
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Wang et al., “Efficient Platform for Synthesizing Comprehensive Heparan Sulfate Oligosaccharide Libraries for Decoding Glycosaminoglycan-Protein Interactions” Nature Chemistry 2023
DOI: https://doi.org/10.1038/s41557-023-01248-4

Design of HS mimetic glycopolymers
We are also studying how the macromolecular structure of HS GAGs influences their biological activity through the design of novel HS mimetics. Toward this end, we are developing glycopolymers that are more readily synthesized than polysaccharides and have tunable chemical and biological properties. The interactions of these glycosaminoglycan mimetics with proteins are being analyzed to determine the role of specific sulfation patterns and molecular architecture in regulating important biological processes, such as growth factor signaling, inflammation and blood coagulation.​

Small molecule inhibitors
To modulate HS sulfation patterns in vivo we are developing small-molecule inhibitors for GAG sulfotransferases. To discover these molecules, we utilize high-throughput screening (e.g., in silico and in vitro) to identify hit compounds for later validation. Future efforts will focus on inhibitors with a high-level of selectivity between HS sulfotransferases, allowing us to fine tune HS sulfation motifs. These molecules will allow us to interrogate the HS code in complex biological systems and uncover which motifs are involved in processes such as angiogenesis, neuronal tau uptake and cancer metastasis.

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