Galectin-3-Binding Glycomimetics that Strongly Reduce Bleomycin-Induced Lung Fibrosis and Modulate Intracellular Glycan Recognition

Autor: Bader A. Salameh, Hans Thalsgaard Schambye, Santanu Mandal, Gunjan Sharma, Ulf J. Nilsson, Alison C. MacKinnon, John Stegmayr, Monique van Scherpenzeel, Amaia Larumbe, P.M. Collins, Vishal Kumar Rajput, Barbro Kahl-Knutsson, Tariq Sethi, Hilde van Hattum, Ian Cumpstey, Roland J. Pieters, Tamara Delaine, Hakon Leffler, Stina Oredsson, Helen Blanchard
Rok vydání: 2016
Předmět:
0301 basic medicine
animal structures
Galectins
Galectin 3
Pulmonary Fibrosis
Molecular Conformation
Administration
Oral
Biology
Bleomycin
01 natural sciences
Biochemistry
03 medical and health sciences
chemistry.chemical_compound
Mice
Structure-Activity Relationship
Fibrosis
Polysaccharides
Pulmonary fibrosis
medicine
otorhinolaryngologic diseases
Animals
Vesicles
Binding site
Molecular Biology
Galectin
Thiodigalactosides
Binding Sites
Dose-Response Relationship
Drug
010405 organic chemistry
Inhibitors
Organic Chemistry
Pirfenidone
medicine.disease
Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3]
0104 chemical sciences
stomatognathic diseases
Disease Models
Animal
030104 developmental biology
chemistry
Galectin-3
Thioglycosides
Molecular Medicine
Antagonists
Medicinal Chemistry
Intracellular
medicine.drug
Zdroj: ChemBioChem; 17(18), pp 1759-1770 (2016)
ChemBioChem, 17, 18, pp. 1759-1770
ChemBioChem, 17, 1759-1770
Delaine, T, Collins, P, MacKinnon, A, Sharma, G, Stegmayr, J, Rajput, V K, Mandal, S, Cumpstey, I, Larumbe, A, Salameh, B A, Kahl-Knutsson, B, van Hattum, H, van Scherpenzeel, M, Pieters, R J, Sethi, T, Schambye, H, Oredsson, S, Leffler, H, Blanchard, H & Nilsson, U J 2016, ' Galectin-3-Binding Glycomimetics that Strongly Reduce Bleomycin-Induced Lung Fibrosis and Modulate Intracellular Glycan Recognition ', ChemBioChem . https://doi.org/10.1002/cbic.201600285
ISSN: 1439-7633
1439-4227
DOI: 10.1002/cbic.201600285
Popis: Discovery of glycan-competitive galectin-3-binding compounds that attenuate lung fibrosis in a murine model and that block intracellular galectin-3 accumulation at damaged vesicles, hence revealing galectin-3-glycan interactions involved in fibrosis progression and in intracellular galectin-3 activities, is reported. 3,3'-Bis-(4-aryltriazol-1-yl)thiodigalactosides were synthesized and evaluated as antagonists of galectin-1, -2, -3, and -4 N-terminal, -4 C-terminal, -7 and -8 N-terminal, -9 N-terminal, and -9 C-terminal domains. Compounds displaying low-nanomolar affinities for galectins-1 and -3 were identified in a competitive fluorescence anisotropy assay. X-ray structural analysis of selected compounds in complex with galectin-3, together with galectin-3 mutant binding experiments, revealed that both the aryltriazolyl moieties and fluoro substituents on the compounds are involved in key interactions responsible for exceptional affinities towards galectin-3. The most potent galectin-3 antagonist was demonstrated to act in an assay monitoring galectin-3 accumulation upon amitriptyline-induced vesicle damage, visualizing a biochemically/medically relevant intracellular lectin-carbohydrate binding event and that it can be blocked by a small molecule. The same antagonist administered intratracheally attenuated bleomycin-induced pulmonary fibrosis in a mouse model with a dose/response profile comparing favorably with that of oral administration of the marketed antifibrotic compound pirfenidone.
Databáze: OpenAIRE
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