The Experts below are selected from a list of 303 Experts worldwide ranked by ideXlab platform
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.
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.
J Ticehurst - 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.
Christopher W Cairo - One of the best experts on this subject based on the ideXlab platform.
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molecular dynamics simulations of Viral Neuraminidase inhibitors with the human Neuraminidase enzymes insights into isoenzyme selectivity
Bioorganic & Medicinal Chemistry, 2018Co-Authors: Michele R Richards, Tianlin Guo, Carmanah D Hunter, Christopher W CairoAbstract:Abstract Inhibitors of Viral Neuraminidase enzymes have been previously developed as therapeutics. Humans can express multiple forms of Neuraminidase enzymes (NEU1, NEU2, NEU3, NEU4) that share a similar active site and enzymatic mechanism with their Viral counterparts. Using a panel of purified human Neuraminidase enzymes, we tested the inhibitory activity of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA), zanamivir, oseltamivir, and peramivir against each of the human isoenzymes. We find that, with the exceptions of DANA and zanamivir, these compounds show generally poor activity against the human Neuraminidase enzymes. To provide insight into the interactions of Viral inhibitors with human Neuraminidases, we conducted molecular dynamics simulations using homology models based on coordinates reported for NEU2. Simulations revealed that an organized water is displaced by zanamivir in binding to NEU2 and NEU3 and confirmed the critical importance of engaging the binding pocket of the C7–C9 glycerol sidechain. Our results suggest that compounds designed to target the human Neuraminidases should provide more selective tools for interrogating these enzymes. Furthermore, they emphasize a need for additional structural data to enable structure-based drug design in these systems.
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inhibitor selectivity of a new class of oseltamivir analogs against Viral Neuraminidase over human Neuraminidase enzymes
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Amgad Albohy, Sankar Mohan, Ruixiang Blake Zheng, Mario B Pinto, Christopher W CairoAbstract:The Viral Neuraminidase enzyme is an established target for anti-influenza pharmaceuticals. However, Viral Neuraminidase inhibitors could have off-target effects due to interactions with native human Neuraminidase enzymes. We report the activity of a series of known inhibitors of the influenza group-1 Neuraminidase enzyme (N1 subtype) against recombinant forms of the human Neuraminidase enzymes NEU3 and NEU4. These inhibitors were designed to take advantage of an additional enzyme pocket (known as the 150-cavity) near the catalytic site of certain Viral Neuraminidase subtypes (N1, N4 and N8). We find that these modified derivatives have minimal activity against the human enzymes, NEU3 and NEU4. Two compounds show moderate activity against NEU3, possibly due to alternative binding modes available to these structures. Our results reinforce that recognition of the glycerol side-chain is distinct between the Viral and human NEU enzymes, and provide experimental support for improving the selectivity of Viral Neuraminidase inhibitors by exploiting the 150-cavity found in certain subtypes of Viral Neuraminidases.
C R Penn - One of the best experts on this subject based on the ideXlab platform.
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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.
