Research output per year
Research output per year
Kristoffer Peterson, Rohit Kumar, Olof Stenström, Priya Verma, Prashant R. Verma, Maria Håkansson, Barbro Kahl-Knutsson, Fredrik Zetterberg, Hakon Leffler, Mikael Akke, Derek T. Logan, Ulf J. Nilsson
Research output: Contribution to journal › Article › peer-review
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.
Original language | English |
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Pages (from-to) | 1164-1175 |
Number of pages | 12 |
Journal | Journal of Medicinal Chemistry |
Volume | 61 |
Issue number | 3 |
DOIs | |
Publication status | Published - 2018 Feb 8 |
Research output: Thesis › Doctoral Thesis (compilation)
Research output: Thesis › Doctoral Thesis (compilation)