Search

Heparan sulfate (HS) is a linear, sulfated and highly negatively-charged polysaccharide that plays important roles in many biological events. As a member of the glycosaminoglycan (GAG) family, HS is commonly found on mammalian cell surfaces and within the extracellular matrix. The structural complexities of natural HS polysaccharides have hampered the comprehension of their biological functions and structure-activity relationships (SARs). Although the sulfation patterns and backbone structures of HS can be major determinants of their biological activities, obtaining significant amounts of pure HS from natural sources for comprehensive SAR studies is challenging. Chemical and enzyme-based synthesis can aid in the production of structurally well-defined HS oligosaccharides. In this review, we discuss recent innovations enabling the syntheses of large libraries of HS and how these libraries can provide insights into the structural preferences of various HS binding proteins., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Xuefei Huang reports financial support was provided by National Institutes of Health. Jian Liu reports financial support was provided by National Institutes of Health. Nicola Pohl reports financial support was provided by National Institutes of Health. Linda Hsieh-wilson reports financial support was provided by National Institutes of Health. Jian Liu reports a relationship with Glycan Therapeutics, LLC that includes: equity or stocks. Xuefei Huang reports a relationship with Glycan Therapeutics, LLC that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Heparan sulfate (HS) has multifaceted biological activities. To date, no libraries of HS oligosaccharides bearing systematically varied sulfation structures are available owing to the challenges in synthesizing a large number of HS oligosaccharides. To overcome the obstacles and expedite the synthesis, a divergent approach was designed, where 64 HS tetrasaccharides covering all possible structures of 2-O-, 6-O- and N-sulfation with the glucosamine-glucuronic acid-glucosamine-iduronic acid backbone were successfully produced from a single strategically protected tetrasaccharide intermediate. This extensive library helped identify the structural requirements for HS sequences to have strong fibroblast growth factor-2 binding but a weak affinity for platelet factor-4. Such a strategy to separate out these two interactions could lead to new HS-based potential therapeutics without the dangerous adverse effect of heparin-induced thrombocytopenia., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Heparan sulfate (HS) has multifaceted biological activities. To date, no libraries of HS oligosaccharides bearing systematically varied sulfation structures are available owing to the challenges in synthesizing a large number of HS oligosaccharides. To overcome the obstacles and expedite the synthesis, a divergent approach was designed, where 64 HS tetrasaccharides covering all possible structures of 2‐O‐, 6‐O‐ and N‐sulfation with the glucosamine‐glucuronic acid‐glucosamine‐iduronic acid backbone were successfully produced from a single strategically protected tetrasaccharide intermediate. This extensive library helped identify the structural requirements for HS sequences to have strong fibroblast growth factor‐2 binding but a weak affinity for platelet factor‐4. Such a strategy to separate out these two interactions could lead to new HS‐based potential therapeutics without the dangerous adverse effect of heparin‐induced thrombocytopenia. [ABSTRACT FROM AUTHOR]

Frontispiece: Synthesis of a Systematic 64-Membered Heparan Sulfate Tetrasaccharide Library Keywords: biological activity; carbohydrates; heparan sulfate; library synthesis; oligosaccharides EN biological activity carbohydrates heparan sulfate library synthesis oligosaccharides 1 1 1 01/02/23 20230102 NES 230102 B Carbohydrates b . In their Research Article (e202211985), Xuefei Huang et al. report the synthesis of a systemic 64-membered heparan sulfate tetrasaccharide library. [Extracted from the article]