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Structural and Biophysical Characterization of C-Glycosylic 1,2-Thiodisaccharides Reveals Determinants of Selective Binding to Galectin-7 and Galectin-8N

Tsagkarakou, Anastasia S. ; Kantsadi, Anastassia L. ; Theodoridou, Vasiliki I. ; Veliotis, Nikolaos ; Lázár, László ; József, János ; Juhász, László ; Kontopidis, George ; Leffler, Hakon LU and Nilsson, Ulf J. LU orcid , et al. (2026) In ChemMedChem 21(16).
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Galectins/metabolism, Humans, Structure-Activity Relationship, Crystallography, X-Ray, Disaccharides/chemistry, Binding Sites, Thermodynamics, Protein Binding, Ligands, Models, Molecular, Molecular Structure
in
ChemMedChem
volume
21
issue
16
article number
e70439
pages
13 pages
publisher
Wiley-Blackwell
external identifiers
  • scopus:105047425016
  • pmid:42603778
ISSN
1860-7187
DOI
10.1002/cmdc.70439
language
English
LU publication?
yes
additional info
© 2026 The Author(s). ChemMedChem published by Wiley‐VCH GmbH.
id
3d760b51-210a-469a-9d96-1912fb7143cd
date added to LUP
2026-08-20 17:22:45
date last changed
2026-09-28 12:05:43
@article{3d760b51-210a-469a-9d96-1912fb7143cd,
  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 (<i>K</i><sub>d</sub> = 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.}},
  author       = {{Tsagkarakou, Anastasia S. and Kantsadi, Anastassia L. and Theodoridou, Vasiliki I. and Veliotis, Nikolaos and Lázár, László and József, János and Juhász, László and Kontopidis, George and Leffler, Hakon and Nilsson, Ulf J. and Somsák, László and Leonidas, Demetres D.}},
  issn         = {{1860-7187}},
  keywords     = {{Galectins/metabolism; Humans; Structure-Activity Relationship; Crystallography, X-Ray; Disaccharides/chemistry; Binding Sites; Thermodynamics; Protein Binding; Ligands; Models, Molecular; Molecular Structure}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{16}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{ChemMedChem}},
  title        = {{Structural and Biophysical Characterization of C-Glycosylic 1,2-Thiodisaccharides Reveals Determinants of Selective Binding to Galectin-7 and Galectin-8N}},
  url          = {{http://dx.doi.org/10.1002/cmdc.70439}},
  doi          = {{10.1002/cmdc.70439}},
  volume       = {{21}},
  year         = {{2026}},
}