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PDBsum entry 5e89
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Sugar binding protein/inhibitor
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PDB id
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5e89
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References listed in PDB file
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Key reference
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Title
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Galectin-3-Binding glycomimetics that strongly reduce bleomycin-Induced lung fibrosis and modulate intracellular glycan recognition.
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Authors
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T.Delaine,
P.Collins,
A.Mackinnon,
G.Sharma,
J.Stegmayr,
V.K.Rajput,
S.Mandal,
I.Cumpstey,
A.Larumbe,
B.A.Salameh,
B.Kahl-Knutsson,
H.Van hattum,
M.Van scherpenzeel,
R.J.Pieters,
T.Sethi,
H.Schambye,
S.Oredsson,
H.Leffler,
H.Blanchard,
U.J.Nilsson.
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Ref.
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Chembiochem, 2016,
17,
1759-1770.
[DOI no: ]
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PubMed id
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Abstract
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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.
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