INVESTIGADORES
MARIÑO Karina Valeria
artículos
Título:
Enzymatic synthesis of non-natural trisaccharides and galactosides; Insights of their interaction with galectins as a function of their structure.
Autor/es:
PORCIUNCULA, DIANA; CAGNONI, ALEJANDRO J; MARIÑO, KARINA V.; FONTANA, CAROLINA; SAENZ-MENDEZ, PATRICIA; IRAZOQUI, GABRIELA; GIACOMINI, CECILIA
Revista:
CARBOHYDRATE RESEARCH
Editorial:
ELSEVIER SCI LTD
Referencias:
Lugar: Amsterdam; Año: 2019 vol. 472 p. 1 - 15
ISSN:
0008-6215
Resumen:
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 -D-Galp-(16)--D-Galp-(14)-D-Glcp (2), a mixture of -DGalp-(16)--D-Glcp-(14)-D-Glcp (5) and -D-Galp-(13)--D-Glcp-(14)-DGlcp (6), and finally benzyl -D-galactopyranoside (9), with reaction yields between 16 and 27%. All the galactosides were purified, and characterized using 1H and 13C nuclearmagnetic 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 -Gal linkage seems to be (14) followed by (13) and (16) for hGal-1, and (14) followed by (16) and (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.