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

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.

Strong Binding of C-Glycosylic1,2-Thiodisaccharides to Galectin-3─Enthalpy-Driven Affinity Enhancement by Water-Mediated Hydrogen Bonds

“…All four inhibitors bind by anchoring their β-galactoside part (referred to as Gly-1; see Table ) at subsite C, forming hydrogen-bond interactions with side-chain atoms of His158, Asn160, Arg162, Asn174, and Glu184 and stacking interactions with the side chain of Trp181. This structural mode of binding of the Gly-1 ring to galectin-3 is very similar to the binding of the galactose ring of lactose, TDG, and most disaccharide ligands to galectin-3. ,− The second sugar ring (referred to as Gly-2; Table ) of all four inhibitors, binds partly at subsite D, with 13 , 14 , 15 , and 17 adopting similar conformations. The dihedrals of the thioglycosidic linkage, O5–C1–C2′–C3′, O5–C1–C2′–C1′, C2–C1–C2′–C3′, and C2–C1–C2′–C1′, have values between 57 to 64°, −133 to −142°, −56 to 66°, and 97 to 105°, respectively.…”

“…4,5,7-Tri- O -acetyl-2,6-anhydro-3-deoxy-3-S-(2,3,4,6-tetra- O -acetyl-β- d -galactopyranosyl)-3-thio- d - glycero - l - altro -heptonamide ( 8 , 80 mg, 0.118 mmol) was reacted according to the general procedure to give 14 (39 mg, 86%). [α] D −8.5 ( c 0.05 in H 2 O); R f 0.06 (CH 2 Cl 2 -MeOH 7:3); 1 H NMR (400 MHz, D 2 O) δ (ppm) 4.39 (d, J = 6.3 Hz, 1H), 4.38 (d, J = 5.6 Hz, 1H), 4.17 (dd, J = 5.2, 3.0 Hz, 1H), 3.96 (d, J = 3.2 Hz, 1H), 3.91–3.89 (m, 1H), 3.88–3.76 (m, 4H), 3.74–3.61 (m, 5H), 3.48 (t, J = 9.6 Hz, 1H). 13 C NMR (101 MHz, DMSO- d 6 ) δ (ppm) 171.0, 86.0, 80.3, 79.1, 78.5, 74.5, 71.0, 68.8, 68.3, 67.8, 61.4, 60.4, 46.1.…”

Interplay of halogen bonding and solvation in protein–ligand binding

“…The immunity- and cancer-related protein galectin-3 presents a rather shallow and amphiphilic ligand binding site that was recently targeted by small lead molecules exploiting a surface-exposed XB interaction to reach nM affinities. 16 , 51 , 52 To understand the basis of the affinity enhancement induced by a solvent-exposed XB, we conducted an extensive structural and thermodynamic study of galectin-3 binding to a systematic series of ligands with increasing halogen size from F to I . All ligands, including the H control ligand, bind in nearly identical poses with their halophenyl rings showing only minor displacements that maintain a close interaction between the halogen and the carbonyl oxygen of Gly182, which keeps the XB distance almost constant from F to I (3.1–3.3 Å).…”

Glycomimetics for the inhibition and modulation of lectins

“…Recently, Bristol Myers Squibb reported novel triazolyl-substituted monosaccharide derivatives, represented by 57, that were identified through molecular modelling and optimized by an in-depth SAR study. 291 The binding mode for these Gal-3 ligands was suggested by molecular modelling and experimentally confirmed in an X-ray co-crystal structure with human Gal-3 (PDB code ). The compounds bind to both mouse and human Gal-3 and show high selectivity for Gal-3 over Gal-1 and Gal-9.…”