Enzymatic synthesis of non-natural trisaccharides and galactosides; Insights of their interaction with galectins as a function of their structure

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Título

Enzymatic synthesis of non-natural trisaccharides and galactosides; Insights of their interaction with galectins as a function of their structure

Tema

ENZIMAS
SINTESIS ENZIMATICA
OLISACARIDOS
GALECTINAS
GALACTOSIDASAS
BIBLIOGRAFIA NACIONAL QUIMICA
2019

Abstract

Galectins are a family of carbohydrate-recognizing proteins that by interacting with specific glycoepitopes can mediate important biological processes, including immune cell homeostasis and activation of tolerogenic circuits. Among the different members of this family, Galectin 1 and 3 have shown pro-tumorigenic effects, being overexpressed in numerous neoplasic diseases, proving to be relevant in tumor immune escape, tumor progression and resistance to drug-induced apoptosis. Thus, generation of specific glycosides that could inhibit their pro-tumorigenic ability by blocking their carbohydrate recognition domain is one of the current major challenges in the field. Considering that galectin-ligand binding strength is closely related to the ligand structure, analysis of this relationship provides valuable information for rational design of high-affinity ligands that could work as effective galectin inhibitors. Taking profit of the ability of glycosidases to catalyze transglycosylation reactions we achieved the enzymatic synthesis of β-d-Galp-(1 → 6)-β-d-Galp-(1 → 4)-d-Glcp (2), a mixture of β-d-Galp-(1 → 6)-β-d-Glcp-(1 → 4)-d-Glcp (5) and β-d-Galp-(1 → 3)-β-d-Glcp-(1 → 4)-d-Glcp (6), and finally benzyl β-d-galactopyranoside (9), with reaction yields between 16 and 27%. All the galactosides were purified, and characterized using 1H and 13C nuclear magnetic resonance spectroscopy. Docking results performed between the synthesized compounds and human Galectin 1 (hGal-1) and human Galectin 3 (hGal-3) showed that the replacement of a glucose moiety linked to the terminal galactose with a galactose moiety, decreases the affinity for these galectins. Moreover, regarding the interglycosidic bond the most favorable β-Gal linkage seems to be β(1 → 4) followed by β(1 → 3) and β(1 → 6) for hGal-1, and β(1 → 4) followed by β(1 → 6) and β(1 → 3) for hGal-3. These results were in accordance with the IC50 values obtained with in vitro solid phase inhibition assays. Therefore, docking results obtained in this work proved to be a very good approximation for predicting binding affinity of novel galactosides.

Autor

Porciúncula González, Cecilia
Cagnoni, Alejandro
Mariño, Karina v.
Fontana, Carolina
Saenz-Méndez, Patricia

Fuente

Carbohydrate Research v. 472, 2019. -- p. 1-15

Editor

Elsevier

Fecha

2019

Derechos

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Formato

PDF

Idioma

Inglés

Tipo

Artículo

Identificador

DOI: 10.1016/j.carres.2018.10.011

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Original Format

PDF
Fecha de agregación
November 18, 2019
Colección
Bibliografía Nacional Química
Tipo de Elemento
Document
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Citación
Porciúncula González, Cecilia, “Enzymatic synthesis of non-natural trisaccharides and galactosides; Insights of their interaction with galectins as a function of their structure,” RIQUIM - Repositorio Institucional de la Facultad de Química - UdelaR, accessed December 14, 2019, http://riquim.fq.edu.uy/items/show/5908.
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