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Using NMR to Dissect the Chemical Space and O-Sulfation Effects within the O- and S-Glycoside Analogues of Heparan Sulfate.

Abstract : 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 O-glycosidic linkages to hydrolytically more stable S-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 O- and S-glycoside analogues, the chemical space occupied by such compounds is explored and described.
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Contributeur : Louise DESSAIVRE Connectez-vous pour contacter le contributeur
Soumis le : vendredi 29 juillet 2022 - 15:17:10
Dernière modification le : vendredi 5 août 2022 - 11:24:58

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Maria C. Z. Meneghetti, Lucy Naughton, Conor O'Shea, Dindet S.-E. Koffi Teki, Vincent Chagnault, et al.. Using NMR to Dissect the Chemical Space and O-Sulfation Effects within the O- and S-Glycoside Analogues of Heparan Sulfate.. ACS Omega, ACS Publications, 2022, 7 (28), pp.24461--24467. ⟨10.1021/acsomega.2c02070⟩. ⟨hal-03740512⟩



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