Authors
Anastasia S Tsagkarakou, Anastassia L Kantsadi, Vasiliki I Theodoridou, Nikolaos Veliotis, László Lázár, János József, László Juhász, George Kontopidis, Hakon Leffler, Ulf J Nilsson, László Somsák, Demetres D Leonidas
Published in
ChemMedChem. Volume 21. Issue 16. Pages e70439. Aug 27, 2026.
Abstract
Achieving isoform selectivity within the galectin family remains a central challenge in glycomimetic drug design due to the highly conserved architecture of their carbohydrate recognition domains. Here, we define the structural and thermodynamic basis of recognition of a series of C-glycosylic 1,2-thiodisaccharides targeting human galectin-7 and the N-terminal domain of galectin-8 (galectin-8N). Using an integrated approach combining fluorescence polarization, isothermal titration calorimetry, and high-resolution X-Ray crystallography, we establish a clear structure-activity relationship across the ligand series. Compound 17 emerges as the most potent galectin-8N ligand (Kd = 13 μM), outperforming thiodigalactoside, while compound 13 shows preferential binding to galectin-7, demonstrating tunable isoform bias. Structural analysis reveals a conserved anchoring mechanism in which the β-galactoside unit (Gly-1) drives affinity through a rigid hydrogen-bonding and π-stacking network, whereas the second sugar (Gly-2) modulates potency by adopting distinct orientations in galectin-specific extended binding sites. Notably, ligand binding converges on conserved motifs while leaving nonconserved regions unexploited, highlighting clear opportunities for structure-guided optimization. Collectively, this work establishes C-glycosylic thiodisaccharides as a robust platform for selective galectin targeting and provides actionable design principles for next-generation inhibitors.
PMID:
42603778
Bibliographic data and abstract were imported from PubMed on 16 Aug 2026.
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