3 years ago

Systematic Tuning of Fluoro-galectin-3 Interactions Provides Thiodigalactoside Derivatives with Single-Digit nM Affinity and High Selectivity

Systematic Tuning
of Fluoro-galectin-3 Interactions
Provides Thiodigalactoside Derivatives with Single-Digit nM Affinity
and High Selectivity
Fredrik Zetterberg, Rohit Kumar, Hakon Leffler, Maria Håkansson, Mikael Akke, Derek T. Logan, Prashant R. Verma, Ulf J. Nilsson, Olof Stenström, Barbro Kahl-Knutsson, Kristoffer Peterson, Priya Verma
Symmetrical and asymmetrical fluorinated phenyltriazolyl-thiodigalactoside derivatives have been synthesized and evaluated as inhibitors of galectin-1 and galectin-3. Systematic tuning of the phenyltriazolyl-thiodigalactosides’ fluoro-interactions with galectin-3 led to the discovery of inhibitors with exceptional affinities (Kd down to 1–2 nM) in symmetrically substituted thiodigalactosides as well as unsurpassed combination of high affinity (Kd 7.5 nM) and selectivity (46-fold) over galectin-1 for asymmetrical thiodigalactosides by carrying one trifluorphenyltriazole and one coumaryl moiety. Studies of the inhibitor–galectin complexes with isothermal titration calorimetry and X-ray crystallography revealed the importance of fluoro-amide interaction for affinity and for selectivity. Finally, the high affinity of the discovered inhibitors required two competitive titration assay tools to be developed: a new high affinity fluorescent probe for competitive fluorescent polarization and a competitive ligand optimal for analyzing high affinity galectin-3 inhibitors with competitive isothermal titration calorimetry.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b01626

DOI: 10.1021/acs.jmedchem.7b01626

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