Glycopolymer Inhibitors of Galectin‑3 Suppress the Markers of Tissue Remodeling in Pulmonary Hypertension

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 st...

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Veröffentlicht in:Journal of medicinal chemistry 2024-06, Vol.67 (11), p.9214-9226
Hauptverfasser: Sedlář, Antonín, Vrbata, David, Pokorná, Kateřina, Holzerová, Kristýna, Červený, Jakub, Kočková, Olga, Hlaváčková, Markéta, Doubková, Martina, Musílková, Jana, Křen, Vladimír, Kolář, František, Bačáková, Lucie, Bojarová, Pavla
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Sprache:eng
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Zusammenfassung: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.
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.4c00341