Investigation of the Molecular Details of the Interactions of Selenoglycosides and Human Galectin-3

Abstract

Human galectin-3 (hGal-3) is involved in a variety of biological processes and is implicated in wide range of diseases. As a result, targeting hGal-3 for clinical applications has become an intense area of research. As a step towards the development of novel hGal-3 inhibitors, we describe a study of the binding of two Se-containing hGal-3 inhibitors, specifically that of di(β-D-galactopyranosyl)selenide (SeDG), in which two galactose rings are linked by one Se atom and a di(β-D-galactopyranosyl)diselenide (DSeDG) analogue with a diseleno bond between the two sugar units. The binding affinities of these derivatives to hGal-3 were determined by 15N-1H HSQC NMR spectroscopy and fluorescence anisotropy titrations in solution, indicating a slight decrease in the strength of interaction for SeDG compared to thiodigalactoside (TDG), a well-known inhibitor of hGal-3, while DSeDG displayed a much weaker interaction strength. NMR and FA measurements showed that both seleno derivatives bind to the canonical S face site of hGal-3 and stack against the conserved W181 residue also confirmed by X-ray crystallography, revealing canonical properties of the interaction. The interaction with DSeDG revealed two distinct binding modes in the crystal structure which are in fast exchange on the NMR time scale in solution, explaining a weaker interaction with hGal-3 than SeDG. Using molecular dynamics simulations, we have found that energetic contributions to the binding enthalpies mainly differ in the electrostatic interactions and in polar solvation terms and are responsible for weaker binding of DSeDG compared to SeDG. Selenium-containing carbohydrate inhibitors of hGal-3 showing canonical binding modes offer the potential of becoming novel hydrolytically stable scaffolds for a new class of hGal-3 inhibitors.

Exploring the Molecular Interactions of Symmetrical and Unsymmetrical Selenoglycosides with Human Galectin-1 and Galectin-3

“…Recently, only the binding between Gal-3 CRD and two Se-containing Gal-3 inhibitors, specifically SeDG and (di-D-galactopyranosyl) diselenide (DSeDG) analogue with a diselenide bond between the two sugar units, was reported, showing that DSeDG displayed less affinity than SeDG. By means of MD simulations, the difference in the binding of DSeDG and SeDG with Gal-3 was justified by different energetic contributions to the binding enthalpies due to electrostatic interactions and polar solvation terms [ 12 ]. Such data was confirmed by our results obtained with SeDG.…”

“…Successively, the introduction of selenium as the bridging atom in place of sulfur created a new version of diglycosylated analogues characterized by a selenoglycoside bond between two galactose units (SeDG) [ 9 , 10 ]. This modification proved to be a winning move not only because selenium has been incorporated into carbohydrates to assist in X-ray crystal structure determination using single/multiple wavelength anomalous diffraction techniques [ 11 ] and in NMR studies [ 12 ] but mainly due to its enhanced protease stability and its inherent antioxidant and peroxidant properties [ 10 ]. Furthermore, we have recently featured a new version of SeDG, introducing a lipophilic benzyl group at C-3 of both sugar residues [ 10 ] that was revealed to bind both Gal-3 CRD and Gal-9N CRD and showed anti-proliferative and anti-migration effects on a melanoma cell line and anti-angiogenesis activities.…”

Organic selenocompounds: are they the panacea for human illnesses?

“…Based on the recent and extensive research in the field of OSeCs with potential pharmacological uses, we can cite here a few examples such as chiral N-heterocyclic diselenides, 156 selenium-N-heterocyclic carbene adducts, 157 probucol analogues, 158,159 dithiaspiroselenuranes, 160 methylene blue-selenocarbamate, 161 di(β- d -galactopyranosyl)diselenide (DSeDG), 162 selenourea, and isoselenocyanate non-steroidal anti-inflammatory drugs derivatives with in vitro anti-cancer activities. 163 Similarly, diselenides and selenophenes have antioxidant, antitumoral, antibacterial, anticonvulsant, anti-depressant, and anti-inflammatory activities.…”

Synthesis of fluoro- and seleno-containing d-lactose and d-galactose analogues

“…The mixture was left stirring at room temperature 17 hours, then it was neutralized with Dowex 50WX80 cationic resin, filtered, and concentrated in vacuo. 4H, H-6a, H-6b, H-6′ a, H-6′b), 3.71-3.65 (m, 1H, H-5), 3.65-3.59 (m, 1H, H-3), 3.57 (s, 3H, OCH 3 ), 3.45 (atd, J = 6.5, 6.1, 1.2 Hz, 1H, H-5′), 3.27 (at, J = 11.1 Hz, 1H, H-4), 2.14 (s, 3H, OCOCH 3 ), 2.00 (s, 3H, OCOCH 3 ), 1.98-1.96 (m, 6H, 2 OCOCH 3 ); 13 (26). Isoselenouronium salt 13 (52 mg, 97 μmol) and derivative 25 (100 mg, 0.24 mmol) were dissolved in CH 3 CN (2 mL) and Et 3 N (30 μL, 0.24 mmol) was subsequently added.…”

“…17 Adding to the list of chemical modifications for the elucidation of carbohydratelectin interactions is the introduction of a selenium atom, which has also very favourable physical properties for structural analysis. Selenium derivatives of carbohydrate ligands, most often methyl selenoglycosides, have been used as substrates for glycosidase inhibition (similarly to S-linked carbohydrates 22 ), 23 as ligands for plant and mammalian lectins, [24][25][26] in phasing crystal structures of carbohydrate-binding macromolecules, by virtue of the anomalous dispersion of selenium in response to X-ray irradiation, [27][28][29] and, in more recent years, have been employed in NMR studies with 77 Se as the reporting nucleus. [30][31][32][33][34] In fact, the 77 Se isotope has a 1 2 spin, 7.6% natural abundance, and it is particularly sensitive to changes in its local environment, with a large chemical shift range around 3000 ppm.…”