Identification of Monosaccharide Derivatives as Potent, Selective, and Orally Bioavailable Inhibitors of Human and Mouse Galectin‑3

Galectin-3 (Gal-3), a member of the β-galactoside-binding
protein family, is implicated in a wide variety of human diseases.
Identification of Gal-3 inhibitors with the right combination of potency
(against
both human and mouse Gal-3) and pharmacokinetic properties to fully
evaluate the potential of Gal-3 for therapeutic intervention has been
a major challenge due to the characteristics of its binding pocket:
high hydrophilicity and key structural differences between human Gal-3
and the mouse ortholog. We report the discovery of a novel series
of monosaccharide-based, highly potent, and orally bioavailable inhibitors
of human and mouse Gal-3. The novel monosaccharide derivatives proved
to be selective for Gal-3, the only member of the chimeric type of
galectins, over Gal-1 and Gal-9, representative of the prototype and
tandem-repeat type of galectins, respectively. The proposed binding
mode for the newly identified ligands was confirmed by an X-ray cocrystal
structure of a representative analogue bound to Gal-3 protein.