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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Bibtex

@article{31ae47bc5a30414fb55f43c2e9d663e7,
title = "Systematic Tuning of Fluoro-galectin-3 Interactions Provides Thiodigalactoside Derivatives with Single-Digit nM Affinity and High Selectivity",
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.",
author = "Kristoffer Peterson and Rohit Kumar and Olof Stenstr{\"o}m and Priya Verma and Verma, {Prashant R.} and Maria H{\aa}kansson and Barbro Kahl-Knutsson and Fredrik Zetterberg and Hakon Leffler and Mikael Akke and Logan, {Derek T.} and Nilsson, {Ulf J.}",
year = "2018",
month = "2",
day = "8",
doi = "10.1021/acs.jmedchem.7b01626",
language = "English",
volume = "61",
pages = "1164--1175",
journal = "Journal of Medicinal and Pharmaceutical Chemistry",
issn = "1520-4804",
publisher = "The American Chemical Society (ACS)",
number = "3",

}