Meneghetti, Maria CZ, Naughton, Lucy, O'Shea, Conor, Teki, Dindet SE Koffi, Chagnault, Vincent, Nader, Helena B, Rudd, Timothy R, Yates, Edwin A, 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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Using NMR to Dissect the Chemical Space and iOi-Sulfation Effects within the iOi- and iSi-Glycoside Analogues of Heparan Sul.pdf - Published version Download (3MB) | Preview |
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 <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 |
|---|---|
| Uncontrolled Keywords: | 3404 Medicinal and Biomolecular Chemistry, 34 Chemical Sciences |
| 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: | 20 Jun 2024 20:46 |
| DOI: | 10.1021/acsomega.2c02070 |
| Open Access URL: | https://doi.org/10.1021/acsomega.2c02070 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3165562 |
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