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| 2. |
- Peterson, Kristoffer, et al.
(författare)
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Aromatic heterocycle galectin-1 interactions for selective single-digit nM affinity ligands
- 2018
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Ingår i: RSC Advances. - : Royal Society of Chemistry (RSC). - 2046-2069. ; 8:44, s. 24913-24922
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Tidskriftsartikel (refereegranskat)abstract
- A series of 3-triazole-thiogalactosides and 3,3′-triazole-thiodigalactosides substituted with different five-membered heterocycles at the C-4 triazole position were found to have high selectivity for galectin-1. Initial studies on the 3-triazole-thiogalactosides indicated that five membered heterocycles in general gave increased affinity for galectin-1 and improved selectivity over galectin-3. The selectivity profile was similar for thiodigalactosides exemplified by 3,3′ substituted thien-3-yltriazole and thiazol-2-yltriazole, both having single-digit nM galectin-1 affinity and almost 10-fold galectin-1 selectivity. The binding interactions of a thiodigalactoside based galectin-1 inhibitor with two thien-3-yltriazole moieties were studied with X-ray crystallography. One of the thiophene moieties was positioned deeper into the pocket than previously reported phenyltriazoles and formed close contacts with Val31, Ser29, Gly124, and Asp123. The affinity and structural analysis thus revealed that steric and electronic optimization of five-membered aromatic heterocycle binding in a narrow galectin-1 subsite confers high affinity and selectivity.
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| 3. |
- Peterson, Kristoffer, et al.
(författare)
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Systematic Tuning of Fluoro-galectin-3 Interactions Provides Thiodigalactoside Derivatives with Single-Digit nM Affinity and High Selectivity
- 2018
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 61:3, s. 1164-1175
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Tidskriftsartikel (refereegranskat)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.
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| 4. |
- Sörme, Pernilla, et al.
(författare)
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Fluorescence polarization as an analytical tool to evaluate galectin-ligand interactions.
- 2004
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Ingår i: Analytical Biochemistry. - : Elsevier BV. - 1096-0309 .- 0003-2697. ; 334:1, s. 36-47
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Tidskriftsartikel (refereegranskat)abstract
- Galectins are a family of β-galactose binding lectins associated with functions such as immunological and malignant events. To study the binding affinity of galectins for natural and artificial saccharides and glycoconjugates we have developed an assay using fluorescence polarization. A collection of fluorescein-conjugated saccharides was synthesized and used as probes with galectins-1 and -3 and the two carbohydrate recognition domains of galectin-4. Direct binding of a fixed probe amount with different amounts of each galectin defined specificity and selectivity and permitted selection of the optimal probe for inhibition studies. Then fixed amounts of galectin and selected probe were used to screen the inhibitory potency of a library of nonfluorescent compounds. As the assay is in solution and does not require separation of free and bound probe, it is simple and rapid and can easily be applied to different unlabeled galectins. As all interaction components are known, Kd values for galectin–inhibitor interaction can be directly calculated without approximation other than the assumption of a simple one-site competition.
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