The Experts below are selected from a list of 666 Experts worldwide ranked by ideXlab platform
Irina G. Luzina - One of the best experts on this subject based on the ideXlab platform.
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the neu1 selective Sialidase Inhibitor c9 butyl amide dana blocks Sialidase activity and neu1 mediated bioactivities in human lung in vitro and murine lung in vivo
Glycobiology, 2016Co-Authors: Sang W Hyun, Sadagopan Magesh, Alan S. Cross, Avelino C Verceles, Yadagiri Kommagalla, Chandrababunaidu Kona, Hiromune Ando, Irina G. LuzinaAbstract:Neuraminidase-1 (NEU1) is the predominant Sialidase expressed in human airway epithelia and lung microvascular endothelia where it mediates multiple biological processes. We tested whether the NEU1-selective Sialidase Inhibitor, C9-butyl-amide-2-deoxy-2,3-dehydro-N-acetylneuraminic acid (C9-BA-DANA), inhibits one or more established NEU1-mediated bioactivities in human lung cells. We established the IC50 values of C9-BA-DANA for total Sialidase activity in human airway epithelia, lung microvascular endothelia and lung fibroblasts to be 3.74 µM, 13.0 µM and 4.82 µM, respectively. In human airway epithelia, C9-BA-DANA dose-dependently inhibited flagellin-induced, NEU1-mediated mucin-1 ectodomain desialylation, adhesiveness for Pseudomonas aeruginosa and shedding. In lung microvascular endothelia, C9-BA-DANA reversed NEU1-driven restraint of cell migration into a wound and disruption of capillary-like tube formation. NEU1 and its chaperone/transport protein, protective protein/cathepsin A (PPCA), were differentially expressed in these same cells. Normalized NEU1 protein expression correlated with total Sialidase activity whereas PPCA expression did not. In contrast to eukaryotic Sialidases, C9-BA-DANA exerted far less Inhibitory activity for three selected bacterial neuraminidases (IC50 > 800 µM). Structural modeling of the four human Sialidases and three bacterial neuraminidases revealed a loop between the seventh and eighth strands of the β-propeller fold, that in NEU1, was substantially shorter than that seen in the six other enzymes. Predicted steric hindrance between this loop and C9-BA-DANA could explain its selectivity for NEU1. Finally, pretreatment of mice with C9-BA-DANA completely protected against flagellin-induced increases in lung Sialidase activity. Our combined data indicate that C9-BA-DANA inhibits endogenous and ectopically expressed Sialidase activity and established NEU1-mediated bioactivities in human airway epithelia, lung microvascular endothelia, and fibroblasts in vitro and murine lungs in vivo.
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neu1 and neu3 Sialidase activity expressed in human lung microvascular endothelia neu1 restrains endothelial cell migration whereas neu3 does not
Journal of Biological Chemistry, 2012Co-Authors: Alan S. Cross, Alba Mirandaribera, Chiguang Feng, William S. Twaddell, Sang Won Hyun, Irina G. Luzina, Sergei P. Atamas, Chinh Nguyen, Lei Zhang, Wei GuangAbstract:The microvascular endothelial surface expresses multiple molecules whose sialylation state regulates multiple aspects of endothelial function. To better regulate these sialoproteins, we asked whether endothelial cells (ECs) might express one or more catalytically active Sialidases. Human lung microvascular EC lysates contained heat-labile Sialidase activity for a fluorogenic substrate, 2′-(4-methylumbelliferyl)-α-d-N-acetylneuraminic acid (4-MU-NANA), that was dose-dependently inhibited by the competitive Sialidase Inhibitor, 2,3-dehydro-2-deoxy-N-acetylneuraminic acid but not its negative control. The EC lysates also contained Sialidase activity for a ganglioside mixture. Using real time RT-PCR to detect mRNAs for the four known mammalian Sialidases, NEU1, -2, -3, and -4, NEU1 mRNA was expressed at levels 2700-fold higher that those found for NEU2, -3, or -4. Western analyses indicated NEU1 and -3 protein expression. Using confocal microscopy and flow cytometry, NEU1 was immunolocalized to both the plasma membrane and the perinuclear region. NEU3 was detected both in the cytosol and nucleus. Prior siRNA-mediated knockdown of NEU1 and NEU3 each decreased EC Sialidase activity for 4-MU-NANA by >65 and >17%, respectively, and for the ganglioside mixture by 0 and 40%, respectively. NEU1 overexpression in ECs reduced their migration into a wound by >40%, whereas NEU3 overexpression did not. Immunohistochemical studies of normal human tissues immunolocalized NEU1 and NEU3 proteins to both pulmonary and extrapulmonary vascular endothelia. These combined data indicate that human lung microvascular ECs as well as other endothelia express catalytically active NEU1 and NEU3. NEU1 restrains EC migration, whereas NEU3 does not.
M H Dempsey - One of the best experts on this subject based on the ideXlab platform.
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gg167 4 guanidino 2 4 dideoxy 2 3 dehydro n acetylneuraminic acid is a potent Inhibitor of influenza virus in ferrets
Antimicrobial Agents and Chemotherapy, 1995Co-Authors: D M Ryan, J Ticehurst, M H DempseyAbstract:GG167 (4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid) is a novel viral neuraminidase (Sialidase) Inhibitor which, following intranasal administration in ferrets, is at least 100 to 1,000 times more effective than ribavirin and amantadine against influenza A and B viruses. It retains its activity even when treatments are delayed until 24 h postinfection and has no effect on the serum antibody response to infection.
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inhibition of influenza virus replication in mice by gg167 4 guanidino 2 4 dideoxy 2 3 dehydro n acetylneuraminic acid is consistent with extracellular activity of viral neuraminidase Sialidase
Antimicrobial Agents and Chemotherapy, 1994Co-Authors: D M Ryan, J Ticehurst, M H Dempsey, C R PennAbstract:We demonstrate the potent antiviral activity of a novel viral neuraminidase (Sialidase) Inhibitor, 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid (GG167), administered by the intranasal route in comparison with those of amantadine and ribavirin in experimental respiratory tract infections induced with influenza A and B viruses. In an extended study in which mice were infected (day 0) with influenza A/Singapore/1/57 virus, with treatments given prophylactically plus twice daily over days 0 to 3 and with mice observed to day 10, we show that intranasally administered GG167 at 0.4 and 0.01 mg/kg of body weight per dose reduced mortality, lung consolidation, and virus titers in the lung, with no virus growing back following the cessation of treatment. In other studies with influenza B/Victoria/102/85 virus in which infected mice were culled after the cessation of treatment, the calculated intranasal dose required to reduce virus titers in the lungs of treated animals to 10% of that seen in untreated controls (EDAUC10 [where AUC is area under the virus titer days curve]) was 0.085 mg/kg per dose. GG167 was inactive against influenza viruses A and B when given by the intraperitoneal or oral route (EDAUC10, > 100 mg/kg per dose). GG167 was metabolically stable, with an elimination half-life of 10 min following intravenous administration. While readily bioavailable by systemic routes, it was poorly bioavailable by the oral route. Its potent efficacy by the intranasal route but lack of efficacy by other routes, relative to those of amantadine and ribavirin, was explicable in terms of its in vitro activity, bioavailability, and pharmacokinetic properties and with the extracellular activity of viral Sialidase.
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Inhibition of Influenza Virus Replication in Mice by GG167 (4-Guanidino-2,4-Dideoxy-2,3-Dehydro-N-Acetylneuraminic Acid) Is Consistent with Extracellular Activity of
1994Co-Authors: Viral Neuraminidase, J Ticehurst, M H Dempsey, Michael D. Ryan, R. PennAbstract:We demonstrate the potent antiviral activity of a novel viral neuraminidase (Sialidase) Inhibitor, 4-gua-nidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid (GG167), administered by the intranasal route in comparison with those of amantadine and ribavirin in experimental respiratory tract infections induced with influenza A and B viruses. In an extended study in which mice were infected (day 0) with influenza A/Singapore/1/57 virus, with treatments given prophylactically plus twice daily over days 0 to 3 and with mice observed to day 10, we show that intranasally administered GG167 at 0.4 and 0.01 mg/kg of body weight per dose reduced mortality, lung consolidation, and virus titers in the lung, with no virus growing back following the cessation of treatment. In other studies with influenza B/Victoria/102/85 virus in which infected mice were culled after the cessation of treatment, the calculated intranasal dose required to reduce virus titers in the lungs of treated animals to 10 % of that seen in untreated controls (EDAUC,o [where AUC is area under the virus titer days curve]) was 0.085 mg/kg per dose. GG167 was inactive against influenza viruses A and B when given by the intraperitoneal or oral route (EDAUC,0,>100 mg/kg per dose). GG167 was metabolically stable, with an elimination half-life of 10 min following intravenous administration. While readily bioavailable by systemic routes, it was poorly bioavailable by the oral route. Its potent efficacy by the intranasal route but lack of efficacy by other routes, relative to those of amantadine and ribavirin, was explicable in terms of its in vitro activity
D M Ryan - One of the best experts on this subject based on the ideXlab platform.
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gg167 4 guanidino 2 4 dideoxy 2 3 dehydro n acetylneuraminic acid is a potent Inhibitor of influenza virus in ferrets
Antimicrobial Agents and Chemotherapy, 1995Co-Authors: D M Ryan, J Ticehurst, M H DempseyAbstract:GG167 (4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid) is a novel viral neuraminidase (Sialidase) Inhibitor which, following intranasal administration in ferrets, is at least 100 to 1,000 times more effective than ribavirin and amantadine against influenza A and B viruses. It retains its activity even when treatments are delayed until 24 h postinfection and has no effect on the serum antibody response to infection.
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inhibition of influenza virus replication in mice by gg167 4 guanidino 2 4 dideoxy 2 3 dehydro n acetylneuraminic acid is consistent with extracellular activity of viral neuraminidase Sialidase
Antimicrobial Agents and Chemotherapy, 1994Co-Authors: D M Ryan, J Ticehurst, M H Dempsey, C R PennAbstract:We demonstrate the potent antiviral activity of a novel viral neuraminidase (Sialidase) Inhibitor, 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid (GG167), administered by the intranasal route in comparison with those of amantadine and ribavirin in experimental respiratory tract infections induced with influenza A and B viruses. In an extended study in which mice were infected (day 0) with influenza A/Singapore/1/57 virus, with treatments given prophylactically plus twice daily over days 0 to 3 and with mice observed to day 10, we show that intranasally administered GG167 at 0.4 and 0.01 mg/kg of body weight per dose reduced mortality, lung consolidation, and virus titers in the lung, with no virus growing back following the cessation of treatment. In other studies with influenza B/Victoria/102/85 virus in which infected mice were culled after the cessation of treatment, the calculated intranasal dose required to reduce virus titers in the lungs of treated animals to 10% of that seen in untreated controls (EDAUC10 [where AUC is area under the virus titer days curve]) was 0.085 mg/kg per dose. GG167 was inactive against influenza viruses A and B when given by the intraperitoneal or oral route (EDAUC10, > 100 mg/kg per dose). GG167 was metabolically stable, with an elimination half-life of 10 min following intravenous administration. While readily bioavailable by systemic routes, it was poorly bioavailable by the oral route. Its potent efficacy by the intranasal route but lack of efficacy by other routes, relative to those of amantadine and ribavirin, was explicable in terms of its in vitro activity, bioavailability, and pharmacokinetic properties and with the extracellular activity of viral Sialidase.
Chandrababunaidu Kona - One of the best experts on this subject based on the ideXlab platform.
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the neu1 selective Sialidase Inhibitor c9 butyl amide dana blocks Sialidase activity and neu1 mediated bioactivities in human lung in vitro and murine lung in vivo
Glycobiology, 2016Co-Authors: Sang W Hyun, Sadagopan Magesh, Alan S. Cross, Avelino C Verceles, Yadagiri Kommagalla, Chandrababunaidu Kona, Hiromune Ando, Irina G. LuzinaAbstract:Neuraminidase-1 (NEU1) is the predominant Sialidase expressed in human airway epithelia and lung microvascular endothelia where it mediates multiple biological processes. We tested whether the NEU1-selective Sialidase Inhibitor, C9-butyl-amide-2-deoxy-2,3-dehydro-N-acetylneuraminic acid (C9-BA-DANA), inhibits one or more established NEU1-mediated bioactivities in human lung cells. We established the IC50 values of C9-BA-DANA for total Sialidase activity in human airway epithelia, lung microvascular endothelia and lung fibroblasts to be 3.74 µM, 13.0 µM and 4.82 µM, respectively. In human airway epithelia, C9-BA-DANA dose-dependently inhibited flagellin-induced, NEU1-mediated mucin-1 ectodomain desialylation, adhesiveness for Pseudomonas aeruginosa and shedding. In lung microvascular endothelia, C9-BA-DANA reversed NEU1-driven restraint of cell migration into a wound and disruption of capillary-like tube formation. NEU1 and its chaperone/transport protein, protective protein/cathepsin A (PPCA), were differentially expressed in these same cells. Normalized NEU1 protein expression correlated with total Sialidase activity whereas PPCA expression did not. In contrast to eukaryotic Sialidases, C9-BA-DANA exerted far less Inhibitory activity for three selected bacterial neuraminidases (IC50 > 800 µM). Structural modeling of the four human Sialidases and three bacterial neuraminidases revealed a loop between the seventh and eighth strands of the β-propeller fold, that in NEU1, was substantially shorter than that seen in the six other enzymes. Predicted steric hindrance between this loop and C9-BA-DANA could explain its selectivity for NEU1. Finally, pretreatment of mice with C9-BA-DANA completely protected against flagellin-induced increases in lung Sialidase activity. Our combined data indicate that C9-BA-DANA inhibits endogenous and ectopically expressed Sialidase activity and established NEU1-mediated bioactivities in human airway epithelia, lung microvascular endothelia, and fibroblasts in vitro and murine lungs in vivo.
Hiromune Ando - One of the best experts on this subject based on the ideXlab platform.
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the neu1 selective Sialidase Inhibitor c9 butyl amide dana blocks Sialidase activity and neu1 mediated bioactivities in human lung in vitro and murine lung in vivo
Glycobiology, 2016Co-Authors: Sang W Hyun, Sadagopan Magesh, Alan S. Cross, Avelino C Verceles, Yadagiri Kommagalla, Chandrababunaidu Kona, Hiromune Ando, Irina G. LuzinaAbstract:Neuraminidase-1 (NEU1) is the predominant Sialidase expressed in human airway epithelia and lung microvascular endothelia where it mediates multiple biological processes. We tested whether the NEU1-selective Sialidase Inhibitor, C9-butyl-amide-2-deoxy-2,3-dehydro-N-acetylneuraminic acid (C9-BA-DANA), inhibits one or more established NEU1-mediated bioactivities in human lung cells. We established the IC50 values of C9-BA-DANA for total Sialidase activity in human airway epithelia, lung microvascular endothelia and lung fibroblasts to be 3.74 µM, 13.0 µM and 4.82 µM, respectively. In human airway epithelia, C9-BA-DANA dose-dependently inhibited flagellin-induced, NEU1-mediated mucin-1 ectodomain desialylation, adhesiveness for Pseudomonas aeruginosa and shedding. In lung microvascular endothelia, C9-BA-DANA reversed NEU1-driven restraint of cell migration into a wound and disruption of capillary-like tube formation. NEU1 and its chaperone/transport protein, protective protein/cathepsin A (PPCA), were differentially expressed in these same cells. Normalized NEU1 protein expression correlated with total Sialidase activity whereas PPCA expression did not. In contrast to eukaryotic Sialidases, C9-BA-DANA exerted far less Inhibitory activity for three selected bacterial neuraminidases (IC50 > 800 µM). Structural modeling of the four human Sialidases and three bacterial neuraminidases revealed a loop between the seventh and eighth strands of the β-propeller fold, that in NEU1, was substantially shorter than that seen in the six other enzymes. Predicted steric hindrance between this loop and C9-BA-DANA could explain its selectivity for NEU1. Finally, pretreatment of mice with C9-BA-DANA completely protected against flagellin-induced increases in lung Sialidase activity. Our combined data indicate that C9-BA-DANA inhibits endogenous and ectopically expressed Sialidase activity and established NEU1-mediated bioactivities in human airway epithelia, lung microvascular endothelia, and fibroblasts in vitro and murine lungs in vivo.