Galectins are small human proteins participating in inflammation processes, immune response, and cancerogenesis. Tandem-repeat galectins comprising Gal-4, Gal-8, and Gal-9 are a vital yet less studied part of the galectin fingerprint in cancer-related processes. The present work studies a library of prepared multivalent neo-glycoproteins decorated with poly-N-acetyllactosamine and human-milk-type oligosaccharides as ligands of this underexplored family of tandem-repeat galectins. A thorough binding evaluation by ELISA and biolayer interferometry was complemented with a detailed epitope mapping both from the galectin and the glycoconjugate viewpoints by nuclear magnetic resonance. The found interactions in the galectin binding site were correlated to in silico data from molecular modeling. The present work reveals pioneer information on the binding of tandem-repeat galectins to multivalent glycoconjugates carrying complex carbohydrate ligands and represents an invaluable starting point for the development of new high-affinity tailored ligands of tandem-repeat galectins, needed both for diagnosis and therapy.

• MeSH
• galektiny * chemie   metabolismus   MeSH
• glykoproteiny * chemie   metabolismus   MeSH
• lidé MeSH
• ligandy MeSH
• mateřské mléko * chemie   MeSH
• oligosacharidy * chemie   metabolismus   MeSH
• tandemové repetitivní sekvence MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• galektiny * MeSH
• glykoproteiny * MeSH
• ligandy MeSH
• oligosacharidy * MeSH
• poly-N-acetyllactosamine MeSH Prohlížeč
• polysacharidy MeSH

Pulmonary hypertension is a cardiovascular disease with a low survival rate. The protein galectin-3 (Gal-3) binding β-galactosides of cellular glycoproteins plays an important role in the onset and development of this disease. Carbohydrate-based drugs that target Gal-3 represent a new therapeutic strategy in the treatment of pulmonary hypertension. Here, we present the synthesis of novel hydrophilic glycopolymer inhibitors of Gal-3 based on a polyoxazoline chain decorated with carbohydrate ligands. Biolayer interferometry revealed a high binding affinity of these glycopolymers to Gal-3 in the subnanomolar range. In the cell cultures of cardiac fibroblasts and pulmonary artery smooth muscle cells, the most potent glycopolymer 18 (Lac-high) caused a decrease in the expression of markers of tissue remodeling in pulmonary hypertension. The glycopolymers were shown to penetrate into the cells. In a biodistribution and pharmacokinetics study in rats, the glycopolymers accumulated in heart and lung tissues, which are most affected by pulmonary hypertension.

• MeSH
• arteria pulmonalis účinky léků   metabolismus   MeSH
• biologické markery MeSH
• fibroblasty účinky léků   metabolismus   MeSH
• galektin 3 * antagonisté a inhibitory   metabolismus   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• lidé MeSH
• plicní hypertenze * farmakoterapie   metabolismus   MeSH
• polymery chemie   farmakologie   MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické markery MeSH
• galektin 3 * MeSH
• polymery MeSH

Galectins, the glycan binding proteins, and their respective carbohydrate ligands represent a unique fundamental regulatory network modulating a plethora of biological processes. The advances in galectin-targeted therapy must be based on a deep understanding of the mechanism of ligand-protein recognition. Carbosilane dendrimers, the well-defined and finely tunable nanoscaffolds with low toxicity, are promising for multivalent carbohydrate ligand presentation to target galectin receptors. The study discloses a synthetic method for two types of lactose-functionalized carbosilane glycodendrimers (Lac-CS-DDMs). Furthermore, we report their outstanding, dendritic effect-driven affinity to tandem-type galectins, especially Gal-9. In the enzyme-linked immunosorbent assay, the affinity of the third-generation multivalent dendritic ligand bearing 32 lactose units to Gal-9 reached nanomolar values (IC50 = 970 nM), being a 1400-fold more effective inhibitor than monovalent lactose for this protein. This demonstrates a game-changing impact of multivalent presentation on the inhibitory effect of a ligand as simple as lactose. Moreover, using DLS hydrodynamic diameter measurements, we correlated the increased affinity of the glycodendrimer ligands to Gal-3 and Gal-8 but especially to Gal-9 with the formation of relatively uniform and stable galectin/Lac-CS-DDM aggregates.

• MeSH
• galektiny * metabolismus   MeSH
• laktosa * MeSH
• ligandy MeSH
• polysacharidy MeSH
• vazba proteinů MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• carbosilane MeSH Prohlížeč
• galektiny * MeSH
• laktosa * MeSH
• ligandy MeSH
• polysacharidy MeSH

Galectins are carbohydrate-binding lectins that modulate the proliferation, apoptosis, adhesion, or migration of cells by cross-linking glycans on cell membranes or extracellular matrix components. Galectin-4 (Gal-4) is a tandem-repeat-type galectin expressed mainly in the epithelial cells of the gastrointestinal tract. It consists of an N- and a C-terminal carbohydrate-binding domain (CRD), each with distinct binding affinities, interconnected with a peptide linker. Compared to other more abundant galectins, the knowledge of the pathophysiology of Gal-4 is sparse. Its altered expression in tumor tissue is associated with, for example, colon, colorectal, and liver cancers, and it increases in tumor progression, and metastasis. There is also very limited information on the preferences of Gal-4 for its carbohydrate ligands, particularly with respect to Gal-4 subunits. Similarly, there is virtually no information on the interaction of Gal-4 with multivalent ligands. This work shows the expression and purification of Gal-4 and its subunits and presents a structure-affinity relationship study with a library of oligosaccharide ligands. Furthermore, the influence of multivalency is demonstrated in the interaction with a model lactosyl-decorated synthetic glycoconjugate. The present data may be used in biomedical research for the design of efficient ligands of Gal-4 with diagnostic or therapeutic potential.

• Klíčová slova
• blood-group antigen, galectin-4, inhibitor, multivalency, oligosaccharide, transglycosylation,
• MeSH
• galektin 4 * MeSH
• galektiny chemie   MeSH
• lidé MeSH
• ligandy MeSH
• nádory * MeSH
• oligosacharidy chemie   MeSH
• sacharidy MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• galektin 4 * MeSH
• galektiny MeSH
• ligandy MeSH
• oligosacharidy MeSH
• sacharidy MeSH