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<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 <i>K</i><sub>d</sub> values as determined by a competitive fluorescence polarization assay. A detailed thermodynamic analysis of the binding of <span>d</span>-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-<i>O</i>-propargyl-<span>d</span>-galactoside was found to strongly increase the binding enthalpy, whereas the binding of 2-<i>O</i>-carboxymethylene-<span>d</span>-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-<i>O</i>-propargyl-<span>d</span>-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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月24日

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  • Edvin Purić,
  • Mujtaba Hassan,
  • Fredrik Sjövall,
  • Tihomir Tomašič,
  • Mojca Pevec,
  • Jurij Lah,
  • Jaume Adrover Forteza,
  • Anders Sundin,
  • Hakon Leffler,
  • Ulf J. Nilsson,
  • Derek T. Logan,
  • Marko Anderluh

摘要

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 Kd 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.