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Nanomolar inhibitor of the galectin-8 N-terminal domain binds via a non-canonical cation-π interaction

Purić, Edvin ; Hassan, Mujtaba LU ; Sjövall, Fredrik LU orcid ; Tomašič, Tihomir ; Pevec, Mojca ; Lah, Jurij ; Forteza, Jaume Adrover LU ; Sundin, Anders LU ; Leffler, Hakon LU and Nilsson, Ulf J. LU , et al. (2025) In Communications Chemistry 8(1).
Abstract

Galectin-8 is a tandem-repeat galectin consisting of two distinct carbohydrate recognition domains and is a potential drug target. We have developed a library of galectin-8N inhibitors that exhibit high nanomolar K
d values as determined by a competitive fluorescence polarization assay. A detailed thermodynamic analysis of the binding of D-galactosides to galectin-8N by isothermal titration calorimetry reveals important differences in enthalpic and/or entropic contributions to binding. Contrary to expectations, the binding of 2-O-propargyl-D-galactoside was found to strongly increase the binding enthalpy, whereas the binding of 2-O-carboxymethylene-D-galactoside was surprisingly less enthalpy-driven. The results of our work suggest... (More)

Galectin-8 is a tandem-repeat galectin consisting of two distinct carbohydrate recognition domains and is a potential drug target. We have developed a library of galectin-8N inhibitors that exhibit high nanomolar K
d values as determined by a competitive fluorescence polarization assay. A detailed thermodynamic analysis of the binding of D-galactosides to galectin-8N by isothermal titration calorimetry reveals important differences in enthalpic and/or entropic contributions to binding. Contrary to expectations, the binding of 2-O-propargyl-D-galactoside was found to strongly increase the binding enthalpy, whereas the binding of 2-O-carboxymethylene-D-galactoside was surprisingly less enthalpy-driven. The results of our work suggest that the ethynyl group can successfully replace the carboxylate group when targeting the water-exposed guanidine moiety of a critical arginine residue. This results in only a minor loss of affinity and an adjusted enthalpic contribution to the overall binding due to non-canonical cation-π interactions, as evidenced by the obtained crystal structure of 2-O-propargyl-D-galactoside in complex with the N-terminal domain of galectin-8. Such an interaction has neither been identified nor discussed to date in a small-molecule ligand-protein complex.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Communications Chemistry
volume
8
issue
1
article number
59
publisher
Springer Nature
external identifiers
  • scopus:85218681462
  • pmid:39994474
ISSN
2399-3669
DOI
10.1038/s42004-025-01458-6
language
English
LU publication?
yes
additional info
© 2025. The Author(s).
id
708ba829-e61f-474b-9dfc-0b226b37f98c
date added to LUP
2025-02-27 16:08:11
date last changed
2025-08-20 01:26:04
@article{708ba829-e61f-474b-9dfc-0b226b37f98c,
  abstract     = {{<p>Galectin-8 is a tandem-repeat galectin consisting of two distinct carbohydrate recognition domains and is a potential drug target. We have developed a library of galectin-8N inhibitors that exhibit high nanomolar K<br>
 d values as determined by a competitive fluorescence polarization assay. A detailed thermodynamic analysis of the binding of D-galactosides to galectin-8N by isothermal titration calorimetry reveals important differences in enthalpic and/or entropic contributions to binding. Contrary to expectations, the binding of 2-O-propargyl-D-galactoside was found to strongly increase the binding enthalpy, whereas the binding of 2-O-carboxymethylene-D-galactoside was surprisingly less enthalpy-driven. The results of our work suggest that the ethynyl group can successfully replace the carboxylate group when targeting the water-exposed guanidine moiety of a critical arginine residue. This results in only a minor loss of affinity and an adjusted enthalpic contribution to the overall binding due to non-canonical cation-π interactions, as evidenced by the obtained crystal structure of 2-O-propargyl-D-galactoside in complex with the N-terminal domain of galectin-8. Such an interaction has neither been identified nor discussed to date in a small-molecule ligand-protein complex.<br>
 </p>}},
  author       = {{Purić, Edvin and Hassan, Mujtaba and Sjövall, Fredrik and Tomašič, Tihomir and Pevec, Mojca and Lah, Jurij and Forteza, Jaume Adrover and Sundin, Anders and Leffler, Hakon and Nilsson, Ulf J. and Logan, Derek T. and Anderluh, Marko}},
  issn         = {{2399-3669}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{1}},
  publisher    = {{Springer Nature}},
  series       = {{Communications Chemistry}},
  title        = {{Nanomolar inhibitor of the galectin-8 N-terminal domain binds via a non-canonical cation-π interaction}},
  url          = {{http://dx.doi.org/10.1038/s42004-025-01458-6}},
  doi          = {{10.1038/s42004-025-01458-6}},
  volume       = {{8}},
  year         = {{2025}},
}