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

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 journalArticlepeer-review

Abstract

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 languageEnglish
Pages (from-to)1164-1175
Number of pages12
JournalJournal of Medicinal Chemistry
Volume61
Issue number3
DOIs
Publication statusPublished - 2018 Feb 8

Subject classification (UKÄ)

  • Medicinal Chemistry

Fingerprint

Dive into the research topics of 'Systematic Tuning of Fluoro-galectin-3 Interactions Provides Thiodigalactoside Derivatives with Single-Digit nM Affinity and High Selectivity'. Together they form a unique fingerprint.

Cite this