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

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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.
Funding Information
  • Royal Society (IEC\NSFC\201116)
  • UK Research and Innovation (MR/T019522/1)
  • Academy of Medical Sciences (SBF007\100054)
  • Wellcome Trust (SBF007\100054)
  • Funda??o de Amparo ? Pesquisa do Estado de S?o Paulo (17/14179-3, 19/19298-6, 20/04899-1)

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