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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Meneghetti, Maria C. Z. ; Naughton, Lucy ; O'Shea, Conor ; Teki, Dindet S. E. Koffi ; Chagnault, Vincent ; Nader, Helena B. ; Rudd, Timothy R. ; Yates, Edwin A. ; Kovensky, Jose ; Miller, Gavin J. ; Lima, Marcelo A.

• Tipo de documento: Artigo Científico
• Fonte: ACS OMEGA; v. N/A, p. 7-pg., 2022-07-08.

Resumo

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. (AU)

• Processo FAPESP: 20/04899-1 - Interação da proteína de superfície (spike protein) do SARS-CoV-2 com heparina: potencial terapêutico
• Beneficiário: Helena Bonciani Nader
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 17/14179-3 - Tráfego vesicular na biossíntese do heparam sulfato
• Beneficiário: Ivarne Luis dos Santos Tersariol
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 19/19298-6 - Desvendando a influência do tráfego vesicular na regulação da biossíntese do heparam sulfato
• Beneficiário: Maria Cecília Zorél Meneghetti
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado