Enzymatic synthesis of non-natural trisaccharides and galactosides; Insights of their interaction with galectins as a function of their structure.
Carbohydr Res
; 472: 1-15, 2019 Jan 15.
Article
en En
| MEDLINE
| ID: mdl-30428394
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 ß-d-Galp-(1â¯ââ¯6)-ß-d-Galp-(1â¯ââ¯4)-d-Glcp(2), a mixture of ß-d-Galp-(1â¯ââ¯6)-ß-d-Glcp-(1â¯ââ¯4)-d-Glcp(5) and ß-d-Galp-(1â¯ââ¯3)-ß-d-Glcp-(1â¯ââ¯4)-d-Glcp(6), and finally benzyl ß-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 ß-Gal linkage seems to be ß(1â¯ââ¯4) followed by ß(1â¯ââ¯3) and ß(1â¯ââ¯6) for hGal-1, and ß(1â¯ââ¯4) followed by ß(1â¯ââ¯6) and ß(1â¯ââ¯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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Trisacáridos
/
Galectinas
/
Galactósidos
/
Glicósido Hidrolasas
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Carbohydr Res
Año:
2019
Tipo del documento:
Article