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Publication Abstract from PubMed

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-pi 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.

Nanomolar inhibitor of the galectin-8 N-terminal domain binds via a non-canonical cation-pi interaction.,Puric E, Hassan M, Sjovall F, Tomasic T, Pevec M, Lah J, Forteza JA, Sundin A, Leffler H, Nilsson UJ, Logan DT, Anderluh M Commun Chem. 2025 Feb 24;8(1):59. doi: 10.1038/s42004-025-01458-6. PMID:39994474^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.