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

By Chunjian Liu, P. R. Jalagam, Jianxin Feng, Wei Wang, Thiruvenkadam Raja, Mallikarjun Reddy Sura, Raju K V L P Manepalli, Bheema Reddy Aliphedi, Santosh Medavarapu, S. Nair and 16 more. 2022

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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.

Subfields: Immunology, Molecular Biology, Computational Chemistry & Drug Discovery