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.

Department of Analytical Chemistry Faculty of Science Charles University Hlavova 8 Prague 2 CZ 128 43 Czech Republic

Department of Health Care Disciplines and Population Protection Faculty of Biomedical Engineering Czech Technical University Prague nám Sítná 3105 Kladno CZ 272 01 Czech Republic

Laboratory of Analytical Chemistry Institute of Macromolecular Chemistry of the Czech Academy of Sciences Heyrovského nám 1888 Prague 6 CZ 162 00 Czech Republic

Laboratory of Biomaterials and Tissue Engineering Institute of Physiology of the Czech Academy of Sciences Vídeňská 1083 Prague 4 CZ 142 00 Czech Republic

Laboratory of Biotransformation Institute of Microbiology of the Czech Academy of Sciences Vídeňská 1083 Prague 4 CZ 142 00 Czech Republic

Laboratory of Developmental Cardiology Institute of Physiology of the Czech Academy of Sciences Vídeňská 1083 Prague 4 CZ 142 00 Czech Republic

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Mechanisms Controlling the Behavior of Vascular Smooth Muscle Cells in Hypoxic Pulmonary Hypertension