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- Title
Chemoenzymatic synthesis of sulfur-linked sugar polymers as heparanase inhibitors.
- Authors
He, Peng; Zhang, Xing; Xia, Ke; Green, Dixy E.; Baytas, Sultan; Xu, Yongmei; Pham, Truong; Liu, Jian; Zhang, Fuming; Almond, Andrew; Linhardt, Robert J.; DeAngelis, Paul L.
- Abstract
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.
- Subjects
HEPARANASE; POLYMERS; GLYCANS; POLYSACCHARIDES; CARRIER proteins; SUGAR
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-34788-3