Identification of Monosaccharide Derivatives as Potent, Selective, and Orally Bioavailable Inhibitors of Human and Mouse Galectin-3
Chunjian Liu, Prasada Rao Jalagam, Jianxin Feng, Wei Wang, Thiruvenkadam Raja, Mallikarjuna Reddy Sura, Raju K. V. L. P. Manepalli, Bheema Reddy Aliphedi, Santosh Medavarapu, Satheesh K. Nair, Muthalagu Vetrichelvan, Ramesh Natesan, Anuradha Gupta, Brett R. Beno, Manoranjan Panda, Kaushik Ghosh, Jinal K. Shukla, Harinath Sale, Priyanka Haldar, Narasimharaju Kalidindi, Devang Shah, Dipal Patel, Arvind Mathur, Bruce A. Ellsworth, Dong Cheng, Alicia Regueiro‐Ren
Abstract
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.