Protein subtype-targeting through ligand epimerization: Talose-selectivity of galectin-4 and galectin-8

A series of O2 and O3-derivatized methyl β-d-talopyranosides were synthesized and evaluated in vitro as inhibitors of the galactose-binding galectin-1, -2, -3, -4 (N- and C-terminal domains), 8 (N-terminal domain), and 9 (N-terminal domain). Galectin-4C and 8N were found to prefer the d-talopyranose configuration to the natural ligand d-galactopyranose configuration. Derivatization at talose O2 and/or O3 provided selective submillimolar inhibitors for these two galectins.

Graphical abstractGalectin-4 C-terminal domain and galectin-8 N-terminal domain were found to prefer the d-talopyranose configuration to the natural ligand d-galactopyranose configuration. Methyl β-d-talopyranosides derivatized at O2 and O3 were synthesized and discovered to be selective submillimolar inhibitors of galectin-4C and galectin-8N.Figure optionsDownload full-size imageDownload as PowerPoint slide