Chemoenzymatic synthesis of sulfur-linked sugar polymers as heparanase inhibitors

• Published in: Nature communications 2022-12, Vol.13 (1), p.7438-12, Article 7438
• Main 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.
• Format: Article
• Language: English
• Subjects: 631/45/221; 631/45/535/878/1263; 631/61; 639/638/309/2420; 639/638/92/72/1205; Analogs; Binding; Carbohydrates; Chemical synthesis; Copolymerization; Drug development; Glucuronidase; Glycan; Heparan sulfate; Heparin; Humanities and Social Sciences; Humans; Inhibitors; Modulators; Molecular dynamics; multidisciplinary; Polymers; Polysaccharides; Proteins; Saccharides; Science; Science (multidisciplinary); Sugar; Sugars; Sulfhydryl Compounds; Sulfur
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34788-3

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.