Using NMR to Dissect the Chemical Space and O-Sulfation Effects within the <i>O</i>- and <i>S</i>-Glycoside Analogues of Heparan Sulfate

Meneghetti, Maria CZ, Naughton, Lucy, O'Shea, Conor, Teki, Dindet SE Koffi, Chagnault, Vincent, Nader, Helena B, Rudd, Timothy R ORCID: 0000-0003-4434-0333, Yates, Edwin A ORCID: 0000-0001-9365-5433, Kovensky, Jose, Miller, Gavin J
et al (show 1 more authors) (2022) Using NMR to Dissect the Chemical Space and O-Sulfation Effects within the <i>O</i>- and <i>S</i>-Glycoside Analogues of Heparan Sulfate. ACS OMEGA, 7 (28). pp. 24461-24467.

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Heparan sulfate (HS), a sulfated linear carbohydrate that decorates the cell surface and extracellular matrix, is ubiquitously distributed throughout the animal kingdom and represents a key regulator of biological processes and a largely untapped reservoir of potential therapeutic targets. The temporal and spatial variations in the HS structure underpin the concept of "heparanome" and a complex network of HS binding proteins. However, despite its widespread biological roles, the determination of direct structure-to-function correlations is impaired by HS chemical heterogeneity. Attempts to correlate substitution patterns (mostly at the level of sulfation) with a given biological activity have been made. Nonetheless, these do not generally consider higher-level conformational effects at the carbohydrate level. Here, the use of NMR chemical shift analysis, NOEs, and spin-spin coupling constants sheds new light on how different sulfation patterns affect the polysaccharide backbone geometry. Furthermore, the substitution of native <i>O</i>-glycosidic linkages to hydrolytically more stable <i>S</i>-glycosidic forms leads to observable conformational changes in model saccharides, suggesting that alternative chemical spaces can be accessed and explored using such mimetics. Employing a series of systematically modified heparin oligosaccharides (as a proxy for HS) and chemically synthesized <i>O</i>- and <i>S</i>-glycoside analogues, the chemical space occupied by such compounds is explored and described.

Item Type: Article
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 17 Oct 2022 15:50
Last Modified: 18 Oct 2023 07:45
DOI: 10.1021/acsomega.2c02070
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