Chemoenzymatic synthesis of sulfur-linked sugar polymers as heparanase inhibitors

Peng He, Xing Zhang, Ke Xia, Dixy E. Green, Sultan Baytas, Yongmei Xu, Truong Pham, Jian Liu, Fuming Zhang, Andrew Almond, Robert J. Linhardt () and Paul L. DeAngelis ()
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Peng He: Rensselaer Polytechnic Institute
Xing Zhang: Nanjing Normal University
Ke Xia: Rensselaer Polytechnic Institute
Dixy E. Green: University of Oklahoma Health Sciences Center
Sultan Baytas: Rensselaer Polytechnic Institute
Yongmei Xu: University of North Carolina
Truong Pham: University of North Carolina
Jian Liu: University of North Carolina
Fuming Zhang: Rensselaer Polytechnic Institute
Andrew Almond: The University of Manchester
Robert J. Linhardt: Rensselaer Polytechnic Institute
Paul L. DeAngelis: University of Oklahoma Health Sciences Center

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34788-3

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