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

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Systematic Tuning of Fluoro-galectin-3 Interactions Provides Thiodigalactoside Derivatives with Single-Digit nM Affinity and High Selectivity. / Peterson, Kristoffer; Kumar, Rohit; Stenström, Olof; Verma, Priya; Verma, Prashant R.; Håkansson, Maria; Kahl-Knutsson, Barbro; Zetterberg, Fredrik; Leffler, Hakon; Akke, Mikael; Logan, Derek T.; Nilsson, Ulf J.

I: Journal of Medicinal Chemistry, Vol. 61, Nr. 3, 08.02.2018, s. 1164-1175.

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TY - JOUR

T1 - Systematic Tuning of Fluoro-galectin-3 Interactions Provides Thiodigalactoside Derivatives with Single-Digit nM Affinity and High Selectivity

AU - Peterson, Kristoffer

AU - Kumar, Rohit

AU - Stenström, Olof

AU - Verma, Priya

AU - Verma, Prashant R.

AU - Håkansson, Maria

AU - Kahl-Knutsson, Barbro

AU - Zetterberg, Fredrik

AU - Leffler, Hakon

AU - Akke, Mikael

AU - Logan, Derek T.

AU - Nilsson, Ulf J.

PY - 2018/2/8

Y1 - 2018/2/8

N2 - 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.

AB - 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.

U2 - 10.1021/acs.jmedchem.7b01626

DO - 10.1021/acs.jmedchem.7b01626

M3 - Article

VL - 61

SP - 1164

EP - 1175

JO - Journal of Medicinal and Pharmaceutical Chemistry

T2 - Journal of Medicinal and Pharmaceutical Chemistry

JF - Journal of Medicinal and Pharmaceutical Chemistry

SN - 1520-4804

IS - 3

ER -