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Thisbe K. Lindhorst - One of the best experts on this subject based on the ideXlab platform.
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A Photoswitchable Trivalent Cluster Mannoside to Probe the Effects of Ligand Orientation in Bacterial Adhesion.
Chembiochem : a European journal of chemical biology, 2019Co-Authors: Guillaume Despras, Leonhard Möckl, Anne Heitmann, Insa Stamer, Christoph Bräuchle, Thisbe K. LindhorstAbstract:We have recently demonstrated, by employing azobenzene glycosides, that bacterial adhesion to surfaces can be switched through reversible reorientation of the carbohydrate ligands. To investigate this phenomenon further, we have turned here to more complex-that is, multivalent-azobenzene glycoclusters. We report on the synthesis of a photosensitive trivalent cluster Mannoside conjugated to an azobenzene hinge at the focal point. Molecular dynamics studies suggested that this cluster Mannoside, despite the conformational flexibility of the azobenzene-glycocluster linkage, offers the potential for reversibly changing the glycocluster's orientation on a surface. Next, the photoswitchable glycocluster was attached to human cells, and adhesion assays with type 1 fimbriated Escherichia coli bacteria were performed. They showed marked differences in bacterial adhesion, dependent on the light-induced reorientation of the glycocluster moiety. These results further underline the importance of orientational effects in carbohydrate recognition and likewise the value of photoswitchable glycoconjugates for their study.
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Diazirine-functionalized Mannosides for photoaffinity labeling: trouble with FimH.
Beilstein journal of organic chemistry, 2018Co-Authors: Femke Beiroth, Tomas Koudelka, Thorsten Overath, Stefan D. Knight, Andreas Tholey, Thisbe K. LindhorstAbstract:Photoaffinity labeling is frequently employed for the investigation of ligand-receptor interactions in solution. We have employed an interdisciplinary methodology to achieve facile photolabeling of the lectin FimH, which is a bacterial protein, crucial for adhesion, colonization and infection. Following our earlier work, we have here designed and synthesized diazirine-functionalized Mannosides as high-affinity FimH ligands and performed an extensive study on photo-crosslinking of the best ligand (Mannoside 3) with a series of model peptides and FimH. Notably, we have employed high-performance mass spectrometry to be able to detect radiation results with the highest possible accuracy. We are concluding from this study that photolabeling of FimH with sugar diazirines has only very limited success and cannot be regarded a facile approach for covalent modification of FimH.
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Evaluation of the carbohydrate recognition domain of the bacterial adhesin FimH: design, synthesis and binding properties of Mannoside ligands
Organic & biomolecular chemistry, 2006Co-Authors: Oliver Sperling, Andreas Fuchs, Thisbe K. LindhorstAbstract:Fimbriae are proteinogeneous appendages on the surface of bacteria, which mediate bacterial adhesion to the host cell glycocalyx. The so-called type 1 fimbriae exhibit specificity for α-D-Mannosides and, therefore, they are assumed to mediate bacterial adhesion via the interaction of a fimbrial lectin and α-D-mannosyl residues exposed on the host cell surface. This carbohydrate-specific adhesive protein subunit of type 1 fimbriae has been identified as a protein called FimH. The crystal structure of this lectin is known and, based on this information, the molecular details of the interaction of Mannoside ligands and FimH are addressed in this paper. Computer-based docking methods were used to evaluate known ligands as well as to design new ones. Then, a series of new Mannosides with extended aglycon was synthesized and tested as inhibitors of type 1 fimbriae-mediated bacterial adhesion in an ELISA. The results obtained were compared to the predictions and findings as delivered by molecular modeling. This study led to an improved understanding of the ligand–receptor interactions under investigation.
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Synthesis of Cluster Mannosides Carrying a Photolabile Diazirine Group
European Journal of Organic Chemistry, 2006Co-Authors: Mark Walter, Michaela Wiegand, Thisbe K. LindhorstAbstract:We are investigating the mechanisms underlying the carbohydrate-specific adhesion of bacteria such as Escherichia coli to the glycocalyx of their potential host cells. E. coli possess protein appendages, which are called type 1 fimbriae. Part of type 1 fimbriae is a protein named FimH, which is a mannose-specific lectin. We wish to use photoaffinity labeling to elucidate mannose binding sites on FimH. Thus we report the synthesis of di- and trivalent cluster Mannosides, which carry a photolabile diazirine group. The diazirine group was introduced by a convergent approach using thiourea bridging (products 6, 13, 17, and 27) or in a divergent synthesis leading to the divalent cluster Mannoside 31. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
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Trivalent cluster Mannosides with aromatic partial structure as ligands for the type 1 fimbrial lectin of Escherichia coli
Australian Journal of Chemistry, 2002Co-Authors: Niels Röckendorf, Oliver Sperling, Thisbe K. LindhorstAbstract:Mannose-specific adhesion of E. coli bacteria to their host cells is mediated by so-called type 1 fimbriae containing lectin domains present on the type 1 fimbrial FimH protein. The crystal structure of a FimH-FimC(chaperone) protein complex revealed a number of amino acids in the carbohydrate binding site with aromatic side chains. This finding is in keeping with earlier results showing high inhibitory potencies of aryl Mannosides when tested as inhibitors of type 1 fimbriae-mediated bacterial adhesion. In addition, clustering of mannosyl moieties also led to favourable effects, as in the case of trivalent cluster Mannosides such as (1). In order to combine both, i.e. the clustering approach and the advantage of an aromatic moiety, the herein presented study has emphasized the synthesis of three cluster Mannosides (2), (3), and (4), as ligands for the type 1 fimbrial lectin, which contain a phenyl partial structure in different proximity to the core of the molecule. The inhibitory potencies of the new cluster Mannosides were determined in enzyme-linked immunosorbent assays (ELISAs).
Dingeman C. Rijken - One of the best experts on this subject based on the ideXlab platform.
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Cluster Mannosides can inhibit mannose receptor-mediated tissue-type plasminogen activator degradation by both rat and human cells
Hepatology, 1997Co-Authors: Femke Noorman, M.m. Barrett-bergshoeff, E. Van De Bilt, Theo J C Van Berkel, Erik A L Biessen, Dingeman C. RijkenAbstract:Abstract Recently, we developed a series of cluster Mannosides that were able to inhibit tissue-type plasminogen activator (t-PA) binding to the isolated mannose receptor. The Mannoside with the highest affinity was able to inhibit t-PA clearance by the liver in the rat. To test whether these Mannosides would also be efficient inhibitors in humans, we studied the expression of the mannose receptor in the human liver and determined the efficacy of the Mannosides to inhibit mannose receptor-mediated t-PA degradation by both rat and human cells. Immunohistochemistry indicates that, like the rat, human liver endothelial cells and human Kupffer cells do express the mannose receptor. The Mannosides do inhibit mannose receptor-mediated t-PA binding, association, and degradation by isolated rat liver endothelial cells and t-PA association and degradation by cultured human macrophages at similar concentrations. The cluster Mannoside with six mannose residues connected with a backbone of five lysine groups (M6L5) was, like unlabeled t-PA, able to inhibit 125I-t-PA degradation in the nmol/L range, while the Mannoside M5L4 inhibited 125I-t-PA degradation in the μmol/L range. The concentrations of Mannoside necessary to inhibit 125I-t-PA degradation in vitro were comparable with the concentrations necessary to inhibit mannose receptor-mediated 125I-t-PA clearance in vivo. We conclude that there is no species difference between rat and humans with respect to the distribution of the mannose receptor in the liver and the affinity of the cluster Mannosides, establishing the relevance of the inhibition of mannose receptor- mediated t-PA clearance by M6L5 as observed in the rat, for the human situation. (Hepatology 1997 Nov;26(5):1303-10)
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Antagonists of the Mannose Receptor and the LDL Receptor–Related Protein Dramatically Delay the Clearance of Tissue Plasminogen Activator
Circulation, 1997Co-Authors: Erik A L Biessen, M.m. Barrett-bergshoeff, Marco Van Teijlingen, H. Vietsch, Martin K Bijsterbosch, Dingeman C. Rijken, Theo J C Van Berkel, Johan KuiperAbstract:Background Clinical application of tissue plasminogen activator (TPA) as a fibrinolytic agent is complicated by its rapid clearance from the bloodstream, which is caused by TPA liver uptake. The mannose receptor on endothelial liver cells and the LDL receptor–related protein (LRP) on parenchymal liver cells were reported to contribute to liver uptake. Methods and Results In this study, we addressed whether TPA clearance can be delayed by inhibiting receptor-mediated endocytosis of TPA. A series of cluster Mannosides was synthesized, and their affinity for the mannose receptor was determined. A cluster Mannoside carrying six mannose groups (M6L5) displayed a subnanomolar affinity for the mannose receptor (Ki=0.41±0.09 nmol/L). Preinjection of M6L5 (1.2 mg/kg) reduced the clearance of 125I-TPA in rats by 60% because of specific inhibition of the endothelial cell uptake. The low toxicity of M6L5, combined with its accessible synthesis and high specificity for the mannose receptor, makes it a promising agent ...
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Cluster Mannosides can inhibit mannose receptor–mediated tissue-type plasminogen activator degradation by both rat and human cells
Hepatology (Baltimore Md.), 1997Co-Authors: Femke Noorman, M.m. Barrett-bergshoeff, Erik A L Biessen, E. Van De Bilt, T. J. C. Van Berkel, Dingeman C. RijkenAbstract:Abstract Recently, we developed a series of cluster Mannosides that were able to inhibit tissue-type plasminogen activator (t-PA) binding to the isolated mannose receptor. The Mannoside with the highest affinity was able to inhibit t-PA clearance by the liver in the rat. To test whether these Mannosides would also be efficient inhibitors in humans, we studied the expression of the mannose receptor in the human liver and determined the efficacy of the Mannosides to inhibit mannose receptor-mediated t-PA degradation by both rat and human cells. Immunohistochemistry indicates that, like the rat, human liver endothelial cells and human Kupffer cells do express the mannose receptor. The Mannosides do inhibit mannose receptor-mediated t-PA binding, association, and degradation by isolated rat liver endothelial cells and t-PA association and degradation by cultured human macrophages at similar concentrations. The cluster Mannoside with six mannose residues connected with a backbone of five lysine groups (M 6 L 5 ) was, like unlabeled t-PA, able to inhibit 125 I-t-PA degradation in the nmol/L range, while the Mannoside M 5 L 4 inhibited 125 I-t-PA degradation in the μmol/L range. The concentrations of Mannoside necessary to inhibit 125 I-t-PA degradation in vitro were comparable with the concentrations necessary to inhibit mannose receptor-mediated 125 I-t-PA clearance in vivo. We conclude that there is no species difference between rat and humans with respect to the distribution of the mannose receptor in the liver and the affinity of the cluster Mannosides, establishing the relevance of the inhibition of mannose receptor- mediated t-PA clearance by M 6 L 5 as observed in the rat, for the human situation. (Hepatology 1997 Nov;26(5):1303-10)
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Lysine-based Cluster Mannosides That Inhibit Ligand Binding to the Human Mannose Receptor at Nanomolar Concentration
Journal of Biological Chemistry, 1996Co-Authors: Erik A L Biessen, Femke Noorman, M.m. Barrett-bergshoeff, Marco Van Teijlingen, Martin K Bijsterbosch, Dingeman C. Rijken, Johan Kuiper, Theo J C Van BerkelAbstract:In search of synthetic high affinity ligands for the mannose receptor, we synthesized a series of lysine-based oligoMannosides containing two (M2L) to six (M6L5) terminal α-D-mannose groups that are connected with the backbone by flexible elongated spacers (16 A). The synthesized cluster Mannosides were all able to displace binding of biotinylated ribonuclease B and tissue-type plasminogen activator to isolated human mannose receptor. The affinity of these cluster Mannosides for the mannose receptor was continuously enhanced from 18-23 μM to 0.5-2.6 nM, with mannose valencies increasing from two to six. On average, expansion of the cluster Mannoside with an additional α-D-mannose group resulted in a 10-fold increase in its affinity for the mannose receptor. M3L2 to M6L5 displayed negative cooperative inhibition of ligand binding to the mannose receptor, suggesting that binding of these Mannosides involves multiple binding sites. The nanomolar affinity of the most potent ligand, the hexaMannoside M6L5 makes it the most potent synthetic cluster Mannoside for the mannose receptor yet developed. As a result of its high affinity and accessible synthesis, M6L5 not only is a powerful tool to study the mechanism of ligand binding by the mannose receptor, but it is also a promising targeting device to accomplish cell-specific delivery of genes and drugs to liver endothelial cells or macrophages in bone marrow, lungs, spleen, and atherosclerotic plaques. Chemicals/CAS: Biotin, 58-85-5; Lectins; Lectins, C-Type; Lysine, 56-87-1; mannose receptor; Mannose-Binding Lectins; oligoMannoside; Oligosaccharides; Receptors, Cell Surface; ribonuclease B, EC 3.1.27.-; Ribonucleases, EC 3.1.-; Tissue Plasminogen Activator, EC 3.4.21.68
Erik A L Biessen - One of the best experts on this subject based on the ideXlab platform.
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Cluster Mannosides can inhibit mannose receptor-mediated tissue-type plasminogen activator degradation by both rat and human cells
Hepatology, 1997Co-Authors: Femke Noorman, M.m. Barrett-bergshoeff, E. Van De Bilt, Theo J C Van Berkel, Erik A L Biessen, Dingeman C. RijkenAbstract:Abstract Recently, we developed a series of cluster Mannosides that were able to inhibit tissue-type plasminogen activator (t-PA) binding to the isolated mannose receptor. The Mannoside with the highest affinity was able to inhibit t-PA clearance by the liver in the rat. To test whether these Mannosides would also be efficient inhibitors in humans, we studied the expression of the mannose receptor in the human liver and determined the efficacy of the Mannosides to inhibit mannose receptor-mediated t-PA degradation by both rat and human cells. Immunohistochemistry indicates that, like the rat, human liver endothelial cells and human Kupffer cells do express the mannose receptor. The Mannosides do inhibit mannose receptor-mediated t-PA binding, association, and degradation by isolated rat liver endothelial cells and t-PA association and degradation by cultured human macrophages at similar concentrations. The cluster Mannoside with six mannose residues connected with a backbone of five lysine groups (M6L5) was, like unlabeled t-PA, able to inhibit 125I-t-PA degradation in the nmol/L range, while the Mannoside M5L4 inhibited 125I-t-PA degradation in the μmol/L range. The concentrations of Mannoside necessary to inhibit 125I-t-PA degradation in vitro were comparable with the concentrations necessary to inhibit mannose receptor-mediated 125I-t-PA clearance in vivo. We conclude that there is no species difference between rat and humans with respect to the distribution of the mannose receptor in the liver and the affinity of the cluster Mannosides, establishing the relevance of the inhibition of mannose receptor- mediated t-PA clearance by M6L5 as observed in the rat, for the human situation. (Hepatology 1997 Nov;26(5):1303-10)
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Antagonists of the Mannose Receptor and the LDL Receptor–Related Protein Dramatically Delay the Clearance of Tissue Plasminogen Activator
Circulation, 1997Co-Authors: Erik A L Biessen, M.m. Barrett-bergshoeff, Marco Van Teijlingen, H. Vietsch, Martin K Bijsterbosch, Dingeman C. Rijken, Theo J C Van Berkel, Johan KuiperAbstract:Background Clinical application of tissue plasminogen activator (TPA) as a fibrinolytic agent is complicated by its rapid clearance from the bloodstream, which is caused by TPA liver uptake. The mannose receptor on endothelial liver cells and the LDL receptor–related protein (LRP) on parenchymal liver cells were reported to contribute to liver uptake. Methods and Results In this study, we addressed whether TPA clearance can be delayed by inhibiting receptor-mediated endocytosis of TPA. A series of cluster Mannosides was synthesized, and their affinity for the mannose receptor was determined. A cluster Mannoside carrying six mannose groups (M6L5) displayed a subnanomolar affinity for the mannose receptor (Ki=0.41±0.09 nmol/L). Preinjection of M6L5 (1.2 mg/kg) reduced the clearance of 125I-TPA in rats by 60% because of specific inhibition of the endothelial cell uptake. The low toxicity of M6L5, combined with its accessible synthesis and high specificity for the mannose receptor, makes it a promising agent ...
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Cluster Mannosides can inhibit mannose receptor–mediated tissue-type plasminogen activator degradation by both rat and human cells
Hepatology (Baltimore Md.), 1997Co-Authors: Femke Noorman, M.m. Barrett-bergshoeff, Erik A L Biessen, E. Van De Bilt, T. J. C. Van Berkel, Dingeman C. RijkenAbstract:Abstract Recently, we developed a series of cluster Mannosides that were able to inhibit tissue-type plasminogen activator (t-PA) binding to the isolated mannose receptor. The Mannoside with the highest affinity was able to inhibit t-PA clearance by the liver in the rat. To test whether these Mannosides would also be efficient inhibitors in humans, we studied the expression of the mannose receptor in the human liver and determined the efficacy of the Mannosides to inhibit mannose receptor-mediated t-PA degradation by both rat and human cells. Immunohistochemistry indicates that, like the rat, human liver endothelial cells and human Kupffer cells do express the mannose receptor. The Mannosides do inhibit mannose receptor-mediated t-PA binding, association, and degradation by isolated rat liver endothelial cells and t-PA association and degradation by cultured human macrophages at similar concentrations. The cluster Mannoside with six mannose residues connected with a backbone of five lysine groups (M 6 L 5 ) was, like unlabeled t-PA, able to inhibit 125 I-t-PA degradation in the nmol/L range, while the Mannoside M 5 L 4 inhibited 125 I-t-PA degradation in the μmol/L range. The concentrations of Mannoside necessary to inhibit 125 I-t-PA degradation in vitro were comparable with the concentrations necessary to inhibit mannose receptor-mediated 125 I-t-PA clearance in vivo. We conclude that there is no species difference between rat and humans with respect to the distribution of the mannose receptor in the liver and the affinity of the cluster Mannosides, establishing the relevance of the inhibition of mannose receptor- mediated t-PA clearance by M 6 L 5 as observed in the rat, for the human situation. (Hepatology 1997 Nov;26(5):1303-10)
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Lysine-based Cluster Mannosides That Inhibit Ligand Binding to the Human Mannose Receptor at Nanomolar Concentration
Journal of Biological Chemistry, 1996Co-Authors: Erik A L Biessen, Femke Noorman, M.m. Barrett-bergshoeff, Marco Van Teijlingen, Martin K Bijsterbosch, Dingeman C. Rijken, Johan Kuiper, Theo J C Van BerkelAbstract:In search of synthetic high affinity ligands for the mannose receptor, we synthesized a series of lysine-based oligoMannosides containing two (M2L) to six (M6L5) terminal α-D-mannose groups that are connected with the backbone by flexible elongated spacers (16 A). The synthesized cluster Mannosides were all able to displace binding of biotinylated ribonuclease B and tissue-type plasminogen activator to isolated human mannose receptor. The affinity of these cluster Mannosides for the mannose receptor was continuously enhanced from 18-23 μM to 0.5-2.6 nM, with mannose valencies increasing from two to six. On average, expansion of the cluster Mannoside with an additional α-D-mannose group resulted in a 10-fold increase in its affinity for the mannose receptor. M3L2 to M6L5 displayed negative cooperative inhibition of ligand binding to the mannose receptor, suggesting that binding of these Mannosides involves multiple binding sites. The nanomolar affinity of the most potent ligand, the hexaMannoside M6L5 makes it the most potent synthetic cluster Mannoside for the mannose receptor yet developed. As a result of its high affinity and accessible synthesis, M6L5 not only is a powerful tool to study the mechanism of ligand binding by the mannose receptor, but it is also a promising targeting device to accomplish cell-specific delivery of genes and drugs to liver endothelial cells or macrophages in bone marrow, lungs, spleen, and atherosclerotic plaques. Chemicals/CAS: Biotin, 58-85-5; Lectins; Lectins, C-Type; Lysine, 56-87-1; mannose receptor; Mannose-Binding Lectins; oligoMannoside; Oligosaccharides; Receptors, Cell Surface; ribonuclease B, EC 3.1.27.-; Ribonucleases, EC 3.1.-; Tissue Plasminogen Activator, EC 3.4.21.68
Theo J C Van Berkel - One of the best experts on this subject based on the ideXlab platform.
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Cluster Mannosides can inhibit mannose receptor-mediated tissue-type plasminogen activator degradation by both rat and human cells
Hepatology, 1997Co-Authors: Femke Noorman, M.m. Barrett-bergshoeff, E. Van De Bilt, Theo J C Van Berkel, Erik A L Biessen, Dingeman C. RijkenAbstract:Abstract Recently, we developed a series of cluster Mannosides that were able to inhibit tissue-type plasminogen activator (t-PA) binding to the isolated mannose receptor. The Mannoside with the highest affinity was able to inhibit t-PA clearance by the liver in the rat. To test whether these Mannosides would also be efficient inhibitors in humans, we studied the expression of the mannose receptor in the human liver and determined the efficacy of the Mannosides to inhibit mannose receptor-mediated t-PA degradation by both rat and human cells. Immunohistochemistry indicates that, like the rat, human liver endothelial cells and human Kupffer cells do express the mannose receptor. The Mannosides do inhibit mannose receptor-mediated t-PA binding, association, and degradation by isolated rat liver endothelial cells and t-PA association and degradation by cultured human macrophages at similar concentrations. The cluster Mannoside with six mannose residues connected with a backbone of five lysine groups (M6L5) was, like unlabeled t-PA, able to inhibit 125I-t-PA degradation in the nmol/L range, while the Mannoside M5L4 inhibited 125I-t-PA degradation in the μmol/L range. The concentrations of Mannoside necessary to inhibit 125I-t-PA degradation in vitro were comparable with the concentrations necessary to inhibit mannose receptor-mediated 125I-t-PA clearance in vivo. We conclude that there is no species difference between rat and humans with respect to the distribution of the mannose receptor in the liver and the affinity of the cluster Mannosides, establishing the relevance of the inhibition of mannose receptor- mediated t-PA clearance by M6L5 as observed in the rat, for the human situation. (Hepatology 1997 Nov;26(5):1303-10)
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Antagonists of the Mannose Receptor and the LDL Receptor–Related Protein Dramatically Delay the Clearance of Tissue Plasminogen Activator
Circulation, 1997Co-Authors: Erik A L Biessen, M.m. Barrett-bergshoeff, Marco Van Teijlingen, H. Vietsch, Martin K Bijsterbosch, Dingeman C. Rijken, Theo J C Van Berkel, Johan KuiperAbstract:Background Clinical application of tissue plasminogen activator (TPA) as a fibrinolytic agent is complicated by its rapid clearance from the bloodstream, which is caused by TPA liver uptake. The mannose receptor on endothelial liver cells and the LDL receptor–related protein (LRP) on parenchymal liver cells were reported to contribute to liver uptake. Methods and Results In this study, we addressed whether TPA clearance can be delayed by inhibiting receptor-mediated endocytosis of TPA. A series of cluster Mannosides was synthesized, and their affinity for the mannose receptor was determined. A cluster Mannoside carrying six mannose groups (M6L5) displayed a subnanomolar affinity for the mannose receptor (Ki=0.41±0.09 nmol/L). Preinjection of M6L5 (1.2 mg/kg) reduced the clearance of 125I-TPA in rats by 60% because of specific inhibition of the endothelial cell uptake. The low toxicity of M6L5, combined with its accessible synthesis and high specificity for the mannose receptor, makes it a promising agent ...
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Lysine-based Cluster Mannosides That Inhibit Ligand Binding to the Human Mannose Receptor at Nanomolar Concentration
Journal of Biological Chemistry, 1996Co-Authors: Erik A L Biessen, Femke Noorman, M.m. Barrett-bergshoeff, Marco Van Teijlingen, Martin K Bijsterbosch, Dingeman C. Rijken, Johan Kuiper, Theo J C Van BerkelAbstract:In search of synthetic high affinity ligands for the mannose receptor, we synthesized a series of lysine-based oligoMannosides containing two (M2L) to six (M6L5) terminal α-D-mannose groups that are connected with the backbone by flexible elongated spacers (16 A). The synthesized cluster Mannosides were all able to displace binding of biotinylated ribonuclease B and tissue-type plasminogen activator to isolated human mannose receptor. The affinity of these cluster Mannosides for the mannose receptor was continuously enhanced from 18-23 μM to 0.5-2.6 nM, with mannose valencies increasing from two to six. On average, expansion of the cluster Mannoside with an additional α-D-mannose group resulted in a 10-fold increase in its affinity for the mannose receptor. M3L2 to M6L5 displayed negative cooperative inhibition of ligand binding to the mannose receptor, suggesting that binding of these Mannosides involves multiple binding sites. The nanomolar affinity of the most potent ligand, the hexaMannoside M6L5 makes it the most potent synthetic cluster Mannoside for the mannose receptor yet developed. As a result of its high affinity and accessible synthesis, M6L5 not only is a powerful tool to study the mechanism of ligand binding by the mannose receptor, but it is also a promising targeting device to accomplish cell-specific delivery of genes and drugs to liver endothelial cells or macrophages in bone marrow, lungs, spleen, and atherosclerotic plaques. Chemicals/CAS: Biotin, 58-85-5; Lectins; Lectins, C-Type; Lysine, 56-87-1; mannose receptor; Mannose-Binding Lectins; oligoMannoside; Oligosaccharides; Receptors, Cell Surface; ribonuclease B, EC 3.1.27.-; Ribonucleases, EC 3.1.-; Tissue Plasminogen Activator, EC 3.4.21.68
M.m. Barrett-bergshoeff - One of the best experts on this subject based on the ideXlab platform.
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Cluster Mannosides can inhibit mannose receptor-mediated tissue-type plasminogen activator degradation by both rat and human cells
Hepatology, 1997Co-Authors: Femke Noorman, M.m. Barrett-bergshoeff, E. Van De Bilt, Theo J C Van Berkel, Erik A L Biessen, Dingeman C. RijkenAbstract:Abstract Recently, we developed a series of cluster Mannosides that were able to inhibit tissue-type plasminogen activator (t-PA) binding to the isolated mannose receptor. The Mannoside with the highest affinity was able to inhibit t-PA clearance by the liver in the rat. To test whether these Mannosides would also be efficient inhibitors in humans, we studied the expression of the mannose receptor in the human liver and determined the efficacy of the Mannosides to inhibit mannose receptor-mediated t-PA degradation by both rat and human cells. Immunohistochemistry indicates that, like the rat, human liver endothelial cells and human Kupffer cells do express the mannose receptor. The Mannosides do inhibit mannose receptor-mediated t-PA binding, association, and degradation by isolated rat liver endothelial cells and t-PA association and degradation by cultured human macrophages at similar concentrations. The cluster Mannoside with six mannose residues connected with a backbone of five lysine groups (M6L5) was, like unlabeled t-PA, able to inhibit 125I-t-PA degradation in the nmol/L range, while the Mannoside M5L4 inhibited 125I-t-PA degradation in the μmol/L range. The concentrations of Mannoside necessary to inhibit 125I-t-PA degradation in vitro were comparable with the concentrations necessary to inhibit mannose receptor-mediated 125I-t-PA clearance in vivo. We conclude that there is no species difference between rat and humans with respect to the distribution of the mannose receptor in the liver and the affinity of the cluster Mannosides, establishing the relevance of the inhibition of mannose receptor- mediated t-PA clearance by M6L5 as observed in the rat, for the human situation. (Hepatology 1997 Nov;26(5):1303-10)
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Antagonists of the Mannose Receptor and the LDL Receptor–Related Protein Dramatically Delay the Clearance of Tissue Plasminogen Activator
Circulation, 1997Co-Authors: Erik A L Biessen, M.m. Barrett-bergshoeff, Marco Van Teijlingen, H. Vietsch, Martin K Bijsterbosch, Dingeman C. Rijken, Theo J C Van Berkel, Johan KuiperAbstract:Background Clinical application of tissue plasminogen activator (TPA) as a fibrinolytic agent is complicated by its rapid clearance from the bloodstream, which is caused by TPA liver uptake. The mannose receptor on endothelial liver cells and the LDL receptor–related protein (LRP) on parenchymal liver cells were reported to contribute to liver uptake. Methods and Results In this study, we addressed whether TPA clearance can be delayed by inhibiting receptor-mediated endocytosis of TPA. A series of cluster Mannosides was synthesized, and their affinity for the mannose receptor was determined. A cluster Mannoside carrying six mannose groups (M6L5) displayed a subnanomolar affinity for the mannose receptor (Ki=0.41±0.09 nmol/L). Preinjection of M6L5 (1.2 mg/kg) reduced the clearance of 125I-TPA in rats by 60% because of specific inhibition of the endothelial cell uptake. The low toxicity of M6L5, combined with its accessible synthesis and high specificity for the mannose receptor, makes it a promising agent ...
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Cluster Mannosides can inhibit mannose receptor–mediated tissue-type plasminogen activator degradation by both rat and human cells
Hepatology (Baltimore Md.), 1997Co-Authors: Femke Noorman, M.m. Barrett-bergshoeff, Erik A L Biessen, E. Van De Bilt, T. J. C. Van Berkel, Dingeman C. RijkenAbstract:Abstract Recently, we developed a series of cluster Mannosides that were able to inhibit tissue-type plasminogen activator (t-PA) binding to the isolated mannose receptor. The Mannoside with the highest affinity was able to inhibit t-PA clearance by the liver in the rat. To test whether these Mannosides would also be efficient inhibitors in humans, we studied the expression of the mannose receptor in the human liver and determined the efficacy of the Mannosides to inhibit mannose receptor-mediated t-PA degradation by both rat and human cells. Immunohistochemistry indicates that, like the rat, human liver endothelial cells and human Kupffer cells do express the mannose receptor. The Mannosides do inhibit mannose receptor-mediated t-PA binding, association, and degradation by isolated rat liver endothelial cells and t-PA association and degradation by cultured human macrophages at similar concentrations. The cluster Mannoside with six mannose residues connected with a backbone of five lysine groups (M 6 L 5 ) was, like unlabeled t-PA, able to inhibit 125 I-t-PA degradation in the nmol/L range, while the Mannoside M 5 L 4 inhibited 125 I-t-PA degradation in the μmol/L range. The concentrations of Mannoside necessary to inhibit 125 I-t-PA degradation in vitro were comparable with the concentrations necessary to inhibit mannose receptor-mediated 125 I-t-PA clearance in vivo. We conclude that there is no species difference between rat and humans with respect to the distribution of the mannose receptor in the liver and the affinity of the cluster Mannosides, establishing the relevance of the inhibition of mannose receptor- mediated t-PA clearance by M 6 L 5 as observed in the rat, for the human situation. (Hepatology 1997 Nov;26(5):1303-10)
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Lysine-based Cluster Mannosides That Inhibit Ligand Binding to the Human Mannose Receptor at Nanomolar Concentration
Journal of Biological Chemistry, 1996Co-Authors: Erik A L Biessen, Femke Noorman, M.m. Barrett-bergshoeff, Marco Van Teijlingen, Martin K Bijsterbosch, Dingeman C. Rijken, Johan Kuiper, Theo J C Van BerkelAbstract:In search of synthetic high affinity ligands for the mannose receptor, we synthesized a series of lysine-based oligoMannosides containing two (M2L) to six (M6L5) terminal α-D-mannose groups that are connected with the backbone by flexible elongated spacers (16 A). The synthesized cluster Mannosides were all able to displace binding of biotinylated ribonuclease B and tissue-type plasminogen activator to isolated human mannose receptor. The affinity of these cluster Mannosides for the mannose receptor was continuously enhanced from 18-23 μM to 0.5-2.6 nM, with mannose valencies increasing from two to six. On average, expansion of the cluster Mannoside with an additional α-D-mannose group resulted in a 10-fold increase in its affinity for the mannose receptor. M3L2 to M6L5 displayed negative cooperative inhibition of ligand binding to the mannose receptor, suggesting that binding of these Mannosides involves multiple binding sites. The nanomolar affinity of the most potent ligand, the hexaMannoside M6L5 makes it the most potent synthetic cluster Mannoside for the mannose receptor yet developed. As a result of its high affinity and accessible synthesis, M6L5 not only is a powerful tool to study the mechanism of ligand binding by the mannose receptor, but it is also a promising targeting device to accomplish cell-specific delivery of genes and drugs to liver endothelial cells or macrophages in bone marrow, lungs, spleen, and atherosclerotic plaques. Chemicals/CAS: Biotin, 58-85-5; Lectins; Lectins, C-Type; Lysine, 56-87-1; mannose receptor; Mannose-Binding Lectins; oligoMannoside; Oligosaccharides; Receptors, Cell Surface; ribonuclease B, EC 3.1.27.-; Ribonucleases, EC 3.1.-; Tissue Plasminogen Activator, EC 3.4.21.68
