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Chemoenzymatic synthesis of sulfur-linked sugar polymers as heparanase inhibitors
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Chemoenzymatic synthesis of sulfur-linked sugar polymers as heparanase inhibitors
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Journal Article
Chemoenzymatic synthesis of sulfur-linked sugar polymers as heparanase inhibitors
2022
Overview
Complex carbohydrates (glycans) are major players in all organisms due to their structural, energy, and communication roles. This last essential role involves interacting and/or signaling through a plethora of glycan-binding proteins. The design and synthesis of glycans as potential drug candidates that selectively alter or perturb metabolic processes is challenging. Here we describe the first reported sulfur-linked polysaccharides with potentially altered conformational state(s) that are recalcitrant to digestion by heparanase, an enzyme important in human health and disease. An artificial sugar donor with a sulfhydryl functionality is synthesized and enzymatically incorporated into polysaccharide chains utilizing heparosan synthase. Used alone, this donor adds a single thio-sugar onto the termini of nascent chains. Surprisingly, in chain co-polymerization reactions with a second donor, this thiol-terminated heparosan also serves as an acceptor to form an unnatural thio-glycosidic bond (‘
S
-link’) between sugar residues in place of a natural ‘
O
-linked’ bond.
S
-linked heparan sulfate analogs are not cleaved by human heparanase. Furthermore, the analogs act as competitive inhibitors with > ~200-fold higher potency than expected; as a rationale, molecular dynamic simulations suggest that the
S
-link polymer conformations mimic aspects of the transition state. Our analogs form the basis for future cancer therapeutics and modulators of protein/sugar interactions.
Heparin is a family of complex carbohydrates binding to proteins to modulate cell activities. Here the authors report the synthesis, and conformations simulations of
S
-linked hemi-A heparosan [GlcA-S-GlcNAc]
n
, a thio-glycosidic uncleavable polysaccharide, and test it as human heparanase inhibitor.
