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Hakon Leffler - One of the best experts on this subject based on the ideXlab platform.
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C1-Galactopyranosyl Heterocycle Structure Guides Selectivity: Triazoles Prefer Galectin‑1 and Oxazoles Prefer Galectin‑3
2019Co-Authors: Alexander Dahlqvist, Hakon Leffler, Ulf J NilssonAbstract:Galectins are carbohydrate-recognizing proteins involved in many different pathological processes, including cancer and immune-related disorders. Inhibitors of galectins have evolved from natural oligosaccharides toward more drug-like truncated galactoside scaffolds that only retain key specific interactions of the galactose scaffolds with the galectin carbohydrate recognition domains. In this context, C1-Galactosides are attractive and stable scaffolds, and this work reports that the synthesis of novel C1-galactopyranosyl heteroaryl derivatives as galectin inhibitors, in which galectin selectivity is governed by the composition of the heterocycle and affinity, is driven by the structure of the aryl substituent to give compounds selective for either galectin-1 or galectin-3. The affinities are close to or better than those of lactose and other natural galectin-binding disaccharides, selectivities induced by the C1-heteroaryl groups are superior to lactose, and compound hydrolytic stabilities and drug-like properties are potentially better than those of natural saccharides. Hence, C1-galactopyranosyl heteroaryls constitute a class of promising starting scaffolds for galectin inhibition, in which a natural ligand pyranose has been replaced by more than fivefold selectivity-inducing heteroaryl rings leading to affinities of 90 μM toward galectin-3 for a C1-galactopyranosyl naphthyloxazole and 170 μM toward galectin-1 for a C1-galactopyranosyl 2-fluorophenyltriazole
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Galectin-3, a marker for vacuole lysis by invasive pathogens.
Cellular Microbiology, 2010Co-Authors: Irit Paz, Hakon Leffler, Martin Sachse, Nicolas Dupont, Joelle Mounier, Cecilia Cederfur, Jost Enninga, Francoise Poirier, Marie-christine Prevost, Frank LafontAbstract:Shigella bacteria invade macrophages and epithelial cells and following internalization lyse the phagosome and escape to the cytoplasm. Galectin-3, an abundant protein in macrophages and epithelial cells, belongs to a family of beta-galactoside-binding proteins, the galectins, with many proposed functions in immune response, development, differentiation, cancer and infection. Galectins are synthesized as cytosolic proteins and following non-classical secretion bind extracellular beta-Galactosides. Here we analysed the localization of galectin-3 following entry of Shigella into the cytosol and detected a striking phenomenon. Very shortly after bacterial invasion, intracellular galectin-3 accumulated in structures in vicinity to internalized bacteria. By using immuno-electron microscopy analysis we identified galectin-3 in membranes localized in the phagosome and in tubules and vesicles that derive from the endocytic pathway. We also demonstrated that the binding of galectin-3 to host N-acetyllactosamine-containing glycans, was required for forming the structures. Accumulation of the structures was a type three secretion system-dependent process. More specifically, existence of structures was strictly dependent upon lysis of the phagocytic vacuole and could be shown also by Gram-positive Listeria and Salmonella sifA mutant. We suggest that galectin-3-containing structures may serve as a potential novel tool to spot vacuole lysis.
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cobalt mediated solid phase synthesis of 3 o alkynylbenzyl Galactosides and their evaluation as galectin inhibitors
Tetrahedron, 2006Co-Authors: Anders Bergh, Hakon Leffler, Ulf J Nilsson, Anders Sundin, Nina KannAbstract:Methyl beta-D-galactoside was converted to the corresponding 3,4-O-stannylene acetal, which was selectively benzylated with 3-iodobenzyl bromide and coupled to a polymer-bound propargylic ether via a Sonogashira reaction. The polymer-bound carbohydrate substrate was cleaved from the resin with different carbon nucleophiles in a cobalt-mediated Nicholas reaction. The product 3-O-alkynylbenzyl Galactosides were screened towards galectin-1, -3, -7, -8N and -9N in a competitive fluorescence polarisation assay. Particularly potent inhibitors were identified against galectin-7 with affinity enhancements up to one order of magnitude due to the 3-O-alkynylbenzyl moiety. (c) 2006 Elsevier Ltd. All rights reserved.
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3 1 2 3 triazol 1 yl 1 thio Galactosides as small efficient and hydrolytically stable inhibitors of galectin 3
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Bader A Salameh, Hakon Leffler, Ulf J NilssonAbstract:Copper(I)-catalyzed addition of alkynes to methyl 3-azido-3-deoxy-1-thio-β-d-galactopyranoside afforded stable and structurally simple 3-deoxy-3-(1H-1,2,3-triazol-1-yl)-1-thio-Galactosides carrying a panel of substituents at the triazole C4 in high yields. The 3-(1H-[1,2,3]-triazol-1-yl)-1-thio-galactoside collection synthesized contained inhibitors of the tumor- and inflammation-related galectin-3 with Kd values as low as 107 μM, which is as potent as the natural disaccharide inhibitors lactose and N-acetyllactosamine.
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The animal lectin galectin-3 interacts with bacterial lipopolysaccharides via two independent sites
Journal of Immunology, 1996Co-Authors: A. Mey, Hakon Leffler, Z. Hmama, G. Normier, J. RevillardAbstract:Galectin-3 is a beta-galactoside binding protein expressed by activated macrophages, epithelial cells, and certain other cell types. Galectin-3 has a C-terminal carbohydrate binding domain, an N-terminal part consisting of a proline- and glycine-rich repetitive domain, and a small N-terminal domain. Two independent LPS binding sites on galectin-3 were demonstrated by binding of biotinylated LPS to immobilized recombinant galectin-3. One appears to be the carbohydrate binding site in the C-terminal domain that confers binding of LPS from Klebsiella pneumoniae that has a p-galactoside-containing polysaccharide chain, This binding is best demonstrated using galectin-3 immunocaptured by a mAb to the N-terminal part (M3/38) and is inhibited by lactose. In contrast, Salmonella minnesota R7 LPS (Rd mutant), which is devoid of beta-Galactosides, appears to bind to a site within the N-terminal part of galectin-3. This interaction is best demonstrated using galectin-3 directly immobilized in wells, and it is inhibited by the Ab M3/38, but not by lactose. Binding inhibition by polymyxin B and the profile of inhibition by a panel of LPSs with different amounts of the inner and outer cores present indicate that this second binding site recognizes the lipid A/inner core region of LPSs.
J. Revillard - One of the best experts on this subject based on the ideXlab platform.
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The animal lectin galectin-3 interacts with bacterial lipopolysaccharides via two independent sites.
Journal of Immunology, 1996Co-Authors: A. Mey, H. Leffler, Z. Hmama, G. Normier, J. RevillardAbstract:Galectin-3 is a beta-galactoside binding protein expressed by activated macrophages, epithelial cells, and certain other cell types. Galectin-3 has a C-terminal carbohydrate binding domain, an N-terminal part consisting of a proline- and glycine-rich repetitive domain, and a small N-terminal domain. Two independent LPS binding sites on galectin-3 were demonstrated by binding of biotinylated LPS to immobilized recombinant galectin-3. One appears to be the carbohydrate binding site in the C-terminal domain that confers binding of LPS from Klebsiella pneumoniae that has a beta-galactoside-containing polysaccharide chain. This binding is best demonstrated using galectin-3 immunocaptured by a mAb to the N-terminal part (M3/38) and is inhibited by lactose. In contrast, Salmonella minnesota R7 LPS (Rd mutant), which is devoid of beta-Galactosides, appears to bind to a site within the N-terminal part of galectin-3. This interaction is best demonstrated using galectin-3 directly immobilized in wells, and it is inhibited by the Ab M3/38, but not by lactose. Binding inhibition by polymyxin B and the profile of inhibition by a panel of LPSs with different amounts of the inner and outer cores present indicate that this second binding site recognizes the lipid A/inner core region of LPSs.
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The animal lectin galectin-3 interacts with bacterial lipopolysaccharides via two independent sites
Journal of Immunology, 1996Co-Authors: A. Mey, Hakon Leffler, Z. Hmama, G. Normier, J. RevillardAbstract:Galectin-3 is a beta-galactoside binding protein expressed by activated macrophages, epithelial cells, and certain other cell types. Galectin-3 has a C-terminal carbohydrate binding domain, an N-terminal part consisting of a proline- and glycine-rich repetitive domain, and a small N-terminal domain. Two independent LPS binding sites on galectin-3 were demonstrated by binding of biotinylated LPS to immobilized recombinant galectin-3. One appears to be the carbohydrate binding site in the C-terminal domain that confers binding of LPS from Klebsiella pneumoniae that has a p-galactoside-containing polysaccharide chain, This binding is best demonstrated using galectin-3 immunocaptured by a mAb to the N-terminal part (M3/38) and is inhibited by lactose. In contrast, Salmonella minnesota R7 LPS (Rd mutant), which is devoid of beta-Galactosides, appears to bind to a site within the N-terminal part of galectin-3. This interaction is best demonstrated using galectin-3 directly immobilized in wells, and it is inhibited by the Ab M3/38, but not by lactose. Binding inhibition by polymyxin B and the profile of inhibition by a panel of LPSs with different amounts of the inner and outer cores present indicate that this second binding site recognizes the lipid A/inner core region of LPSs.
A. Mey - One of the best experts on this subject based on the ideXlab platform.
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The animal lectin galectin-3 interacts with bacterial lipopolysaccharides via two independent sites.
Journal of Immunology, 1996Co-Authors: A. Mey, H. Leffler, Z. Hmama, G. Normier, J. RevillardAbstract:Galectin-3 is a beta-galactoside binding protein expressed by activated macrophages, epithelial cells, and certain other cell types. Galectin-3 has a C-terminal carbohydrate binding domain, an N-terminal part consisting of a proline- and glycine-rich repetitive domain, and a small N-terminal domain. Two independent LPS binding sites on galectin-3 were demonstrated by binding of biotinylated LPS to immobilized recombinant galectin-3. One appears to be the carbohydrate binding site in the C-terminal domain that confers binding of LPS from Klebsiella pneumoniae that has a beta-galactoside-containing polysaccharide chain. This binding is best demonstrated using galectin-3 immunocaptured by a mAb to the N-terminal part (M3/38) and is inhibited by lactose. In contrast, Salmonella minnesota R7 LPS (Rd mutant), which is devoid of beta-Galactosides, appears to bind to a site within the N-terminal part of galectin-3. This interaction is best demonstrated using galectin-3 directly immobilized in wells, and it is inhibited by the Ab M3/38, but not by lactose. Binding inhibition by polymyxin B and the profile of inhibition by a panel of LPSs with different amounts of the inner and outer cores present indicate that this second binding site recognizes the lipid A/inner core region of LPSs.
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The animal lectin galectin-3 interacts with bacterial lipopolysaccharides via two independent sites
Journal of Immunology, 1996Co-Authors: A. Mey, Hakon Leffler, Z. Hmama, G. Normier, J. RevillardAbstract:Galectin-3 is a beta-galactoside binding protein expressed by activated macrophages, epithelial cells, and certain other cell types. Galectin-3 has a C-terminal carbohydrate binding domain, an N-terminal part consisting of a proline- and glycine-rich repetitive domain, and a small N-terminal domain. Two independent LPS binding sites on galectin-3 were demonstrated by binding of biotinylated LPS to immobilized recombinant galectin-3. One appears to be the carbohydrate binding site in the C-terminal domain that confers binding of LPS from Klebsiella pneumoniae that has a p-galactoside-containing polysaccharide chain, This binding is best demonstrated using galectin-3 immunocaptured by a mAb to the N-terminal part (M3/38) and is inhibited by lactose. In contrast, Salmonella minnesota R7 LPS (Rd mutant), which is devoid of beta-Galactosides, appears to bind to a site within the N-terminal part of galectin-3. This interaction is best demonstrated using galectin-3 directly immobilized in wells, and it is inhibited by the Ab M3/38, but not by lactose. Binding inhibition by polymyxin B and the profile of inhibition by a panel of LPSs with different amounts of the inner and outer cores present indicate that this second binding site recognizes the lipid A/inner core region of LPSs.
Ulf J Nilsson - One of the best experts on this subject based on the ideXlab platform.
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C1-Galactopyranosyl Heterocycle Structure Guides Selectivity: Triazoles Prefer Galectin‑1 and Oxazoles Prefer Galectin‑3
2019Co-Authors: Alexander Dahlqvist, Hakon Leffler, Ulf J NilssonAbstract:Galectins are carbohydrate-recognizing proteins involved in many different pathological processes, including cancer and immune-related disorders. Inhibitors of galectins have evolved from natural oligosaccharides toward more drug-like truncated galactoside scaffolds that only retain key specific interactions of the galactose scaffolds with the galectin carbohydrate recognition domains. In this context, C1-Galactosides are attractive and stable scaffolds, and this work reports that the synthesis of novel C1-galactopyranosyl heteroaryl derivatives as galectin inhibitors, in which galectin selectivity is governed by the composition of the heterocycle and affinity, is driven by the structure of the aryl substituent to give compounds selective for either galectin-1 or galectin-3. The affinities are close to or better than those of lactose and other natural galectin-binding disaccharides, selectivities induced by the C1-heteroaryl groups are superior to lactose, and compound hydrolytic stabilities and drug-like properties are potentially better than those of natural saccharides. Hence, C1-galactopyranosyl heteroaryls constitute a class of promising starting scaffolds for galectin inhibition, in which a natural ligand pyranose has been replaced by more than fivefold selectivity-inducing heteroaryl rings leading to affinities of 90 μM toward galectin-3 for a C1-galactopyranosyl naphthyloxazole and 170 μM toward galectin-1 for a C1-galactopyranosyl 2-fluorophenyltriazole
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cobalt mediated solid phase synthesis of 3 o alkynylbenzyl Galactosides and their evaluation as galectin inhibitors
Tetrahedron, 2006Co-Authors: Anders Bergh, Hakon Leffler, Ulf J Nilsson, Anders Sundin, Nina KannAbstract:Methyl beta-D-galactoside was converted to the corresponding 3,4-O-stannylene acetal, which was selectively benzylated with 3-iodobenzyl bromide and coupled to a polymer-bound propargylic ether via a Sonogashira reaction. The polymer-bound carbohydrate substrate was cleaved from the resin with different carbon nucleophiles in a cobalt-mediated Nicholas reaction. The product 3-O-alkynylbenzyl Galactosides were screened towards galectin-1, -3, -7, -8N and -9N in a competitive fluorescence polarisation assay. Particularly potent inhibitors were identified against galectin-7 with affinity enhancements up to one order of magnitude due to the 3-O-alkynylbenzyl moiety. (c) 2006 Elsevier Ltd. All rights reserved.
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3 1 2 3 triazol 1 yl 1 thio Galactosides as small efficient and hydrolytically stable inhibitors of galectin 3
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Bader A Salameh, Hakon Leffler, Ulf J NilssonAbstract:Copper(I)-catalyzed addition of alkynes to methyl 3-azido-3-deoxy-1-thio-β-d-galactopyranoside afforded stable and structurally simple 3-deoxy-3-(1H-1,2,3-triazol-1-yl)-1-thio-Galactosides carrying a panel of substituents at the triazole C4 in high yields. The 3-(1H-[1,2,3]-triazol-1-yl)-1-thio-galactoside collection synthesized contained inhibitors of the tumor- and inflammation-related galectin-3 with Kd values as low as 107 μM, which is as potent as the natural disaccharide inhibitors lactose and N-acetyllactosamine.
H. Ronald Kaback - One of the best experts on this subject based on the ideXlab platform.
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The lactose permease ofEscherichia coli: a paradigm for membrane transport proteins
Biochimica et biophysica acta, 1992Co-Authors: H. Ronald KabackAbstract:The lactose (lac) permease of Escherichia coli is a polytopic cytoplasmic membrane protein that catalyzes the coupled translocation of fl-Galactosides and H + with a stoichiometry of unity (i.e., /3-galactoside/H + symport or cotransport; cf. Refs. 1 and 2 for reviews). The permease has been solubilized from the membrane, purified to homogeneity and reconstituted into phospholipid vesicles in a completely functional state [3,4]. Moreover, the lacY gene has been cloned and sequenced, and the amino-acid sequence of the permease has been deduced from the DNA sequence [5]. Based on circular dichroism and hydropathy analysis of the primary sequence, a secondary-structure was proposed [6] in which the polypeptide has twelve hydrophobic domains in a-helical conformation that traverse the membrane in zigzag fashion connected by hydrophilic loops containing most of the hydrophilic residues. The model is consistent with other spectroscopic measurements [7], chemical modification [8], limited proteolysis [9,10] and immunological studies [11-17], and it has been demonstrated that the Nand C-termini of the permease, as well as loops 5 and 7, are disposed towards the cytoplasmic surface of the membrane. However, none of these approaches is able to differentiate between the 12-helix structure and other models (cf. Ref. 7). Recent analyses of a series of lac permease-alkaline phosphatase (lacY-phoA) fusions [18]
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β-Galactoside Transport in Escherichia Coli: The Ins and Outs of Lactose Permease
Dynamics of Membrane Assembly, 1992Co-Authors: H. Ronald KabackAbstract:Accumulation of β-Galactosides against a concentration gradient in Escherichia coli is carried out by the lactose (lac) permease, a hydrophobic polytopic cytoplasmic membrane protein that catalyzes the coupled translocation of β-Galactosides and H+ with a stoichiometry of unity (i.e. β-galactoside/H+ symport or cotransport) (cf. Kaback, 1983, 1986, 1990 for reviews). Under physiological conditions, where the H+ electrochemical gradient across the cytoplasmic membrane (ΔμH +)1 is interior negative and/or alkaline, lac permease utilizes free energy released from downhill translocation of H+ to drive accumulation of β-Galactosides against a concentration gradient. In the absence of ΔμH +, the permease catalyzes the converse reaction, utilizing free energy from downhill translocation of β-Galactosides to drive uphill translocation of H+ and generating ΔμH +, the polarity of which depends upon the direction of the substrate concentration gradient. As such, lac permease is a paradigm for a wide variety of biological machines in both prokaryotic and eukaryotic membranes that transduce the free energy of an electrochemical ion gradient into work or into other forms of chemical energy (i.e., ATP).
