Chemoenzymatic synthesis of sulfur-linked sugar polymers as heparanase inhibitors
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Published:2022-12-02
Issue:1
Volume:13
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
He PengORCID, Zhang XingORCID, Xia KeORCID, Green Dixy E.ORCID, Baytas SultanORCID, Xu Yongmei, Pham TruongORCID, Liu Jian, Zhang FumingORCID, Almond AndrewORCID, Linhardt Robert J.ORCID, DeAngelis Paul L.ORCID
Abstract
AbstractComplex 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference47 articles.
1. Köwitsch, A., Zhou, G. & Groth, T. Medical application of glycosaminoglycans: a review. J. Tissue Eng. Regen. Med. 12, e23–e41 (2018). 2. Lindahl, U., Couchman, J., Kimata, K. & Esko, J.D. Proteoglycans and Sulfated Glycosaminoglycans in Essentials of Glycobiology, 3rd edition, A. Varki, Ed. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2017) Chapter 17. 3. Esko, J.D., Prestegard, J.H. & Linhardt, R.J. Proteins That Bind Sulfated Glycosaminoglycans Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2015-2017. in Essentials of Glycobiology, 3rd edition, A. Varki, Ed. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2017) Chapter 38. 4. DeAngelis, P. L., Liu, J. & Linhardt, R. J. Chemoenzymatic synthesis of glycosaminoglycans: Re-creating, re-modeling and re-designing nature’s longest or most complex carbohydrate chains. Glycobiology 23, 764–777 (2013). 5. Zhang, X., Lin, L., Huang, H. & Linhardt, R. J. Chemoenzymatic synthesis of glycosaminoglycans. Acc. Chem. Res. 53, 335–346 (2020).
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