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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.

Meneghetti, MCZ; Naughton, L; O'Shea, C; Koffi Teki, DS-E; Chagnault, V; Nader, HB; Rudd, TR; Yates, EA; Kovensky, J; Miller, Gavin; Andrade De Lima, Marcelo

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


Authors

MCZ Meneghetti

L Naughton

C O'Shea

DS-E Koffi Teki

V Chagnault

HB Nader

TR Rudd

EA Yates

J Kovensky



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.

Citation

Meneghetti, M., Naughton, L., O'Shea, C., Koffi Teki, D., Chagnault, V., Nader, H., …Andrade De Lima, M. (2022). Using NMR to Dissect the Chemical Space and O-Sulfation Effects within the O- and S-Glycoside Analogues of Heparan Sulfate. ACS Omega, 7(28), 24461 - 24467. https://doi.org/10.1021/acsomega.2c02070

Journal Article Type Article
Acceptance Date Jun 28, 2022
Online Publication Date Jul 8, 2022
Publication Date Jul 19, 2022
Publicly Available Date Jun 20, 2023
Journal ACS Omega
Electronic ISSN 2470-1343
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 7
Issue 28
Pages 24461 - 24467
DOI https://doi.org/10.1021/acsomega.2c02070
Publisher URL https://pubs.acs.org/doi/10.1021/acsomega.2c02070

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