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Allen Portner - One of the best experts on this subject based on the ideXlab platform.
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the novel Parainfluenza virus hemagglutinin neuraminidase inhibitor bcx 2798 prevents lethal synergism between a paramyxovirus and streptococcus pneumoniae
Antimicrobial Agents and Chemotherapy, 2005Co-Authors: Irina V Alymova, Sudhakara Y Babu, Kelli L. Boyd, Toru Takimoto, Allen Portner, Jonathan A. MccullersAbstract:An association exists between respiratory viruses and bacterial infections. Prevention or treatment of the preceding viral infection is a logical goal for reducing this important cause of morbidity and mortality. The ability of the novel, selective Parainfluenza virus hemagglutinin-neuraminidase inhibitor BCX 2798 to prevent the synergism between a paramyxovirus and Streptococcus pneumoniae was examined in this study. A model of secondary bacterial pneumonia after infection with a recombinant Sendai virus whose hemagglutinin-neuraminidase gene was replaced with that of human Parainfluenza virus type 1 [rSV(hHN)] was established in mice. Challenge of mice with a sublethal dose of S. pneumoniae 7 days after a sublethal infection with rSV(hHN) (synergistic group) caused 100% mortality. Bacterial infection preceding viral infection had no effect on survival. The mean bacterial titers in the synergistic group were significantly higher than in mice infected with bacteria only. The virus titers were similar in mice infected with rSV(hHN) alone and in dually infected mice. Intranasal administration of BCX 2798 at 10 mg/kg per day to the synergistic group of mice starting 4 h before virus infection protected 80% of animals from death. This effect was accompanied by a significant reduction in lung viral and bacterial titers. Treatment of mice 24 h after the rSV(hHN) infection showed no protection against synergistic lethality. Together, our results indicate that Parainfluenza viruses can prime for secondary bacterial infections. Prophylaxis of Parainfluenza virus infections with antivirals might be an effective strategy for prevention of secondary bacterial complications in humans.
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efficacy of novel hemagglutinin neuraminidase inhibitors bcx 2798 and bcx 2855 against human Parainfluenza viruses in vitro and in vivo
Antimicrobial Agents and Chemotherapy, 2004Co-Authors: Irina V Alymova, Sudhakara Y Babu, Chenghong Li, Xiaoping Xiong, Pooran Chand, Toru Takimoto, G. L. Taylor, Allen PortnerAbstract:Human Parainfluenza viruses are important respiratory tract pathogens, especially of children. However, no vaccines or specific therapies for infections caused by these viruses are currently available. In the present study we characterized the efficacy of the novel Parainfluenza virus inhibitors BCX 2798 and BCX 2855, which were designed based on the three-dimensional structure of the hemagglutinin-neuraminidase (HN) protein. The compounds were highly effective in inhibiting hemagglutinin (HA) and neuraminidase (NA) activities and the growth of hPIV-1, hPIV-2, and hPIV-3 in LLC-MK 2 cells. The concentrations required to reduce the activity to 50% of that of a control ranged from 0.1 to 6.0 μM in HA inhibition assays and from 0.02 to 20 μM in NA inhibition assays. The concentrations required to inhibit virus replication to 50% of the level of the control ranged from 0.7 to 11.5 μM. BCX 2798 and BCX 2855 were inactive against influenza virus HA and NA and bacterial NA. In mice infected with a recombinant Sendai virus whose HN gene was replaced with that of hPIV-1 [rSV(hHN)], intranasal administration of BCX 2798 (10 mg/kg per day) and of BCX 2855 (50 mg/kg per day) 4 h before the start of infection resulted in a significant reduction in titers of virus in the lungs and protection from death. Treatment beginning 24 h after the start of infection did not prevent death. Together, our results indicate that BCX 2798 and BCX 2855 are effective inhibitors of Parainfluenza virus HN and may limit Parainfluenza virus infections in humans.
Toru Takimoto - One of the best experts on this subject based on the ideXlab platform.
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Amino acid substitutions contributing to α2,6-sialic acid linkage binding specificity of human Parainfluenza virus type 3 hemagglutinin–neuraminidase
FEBS Letters, 2015Co-Authors: Keijo Fukushima, Masahiro Takaguchi, Hiroo Ueyama, Akira Minami, Hiroaki Tokiwa, Kenta Oishi, Erika Ishitsubo, Tadanobu Takahashi, Toru TakimotoAbstract:Human Parainfluenza virus type 3 (hPIV3) recognizes both α2,3- and α2,6-linked sialic acids, whereas human Parainfluenza virus type 1 (hPIV1) recognizes only α2,3-linked sialic acids. To identify amino acid residues that confer α2,6-linked sialic acid recognition of hPIV3, amino acid residues in or neighboring the sialic acid binding pocket of the hPIV3 hemagglutinin–neuraminidase (HN) glycoprotein were substituted for the corresponding residues of hPIV1 HN. Hemadsorption assay with sialyl linkage-modified red blood cells indicated that amino acid residues at positions 275, 277, 372, and 426 contribute to α2,6-linked sialic acid recognition of the HN3 glycoprotein.
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the novel Parainfluenza virus hemagglutinin neuraminidase inhibitor bcx 2798 prevents lethal synergism between a paramyxovirus and streptococcus pneumoniae
Antimicrobial Agents and Chemotherapy, 2005Co-Authors: Irina V Alymova, Sudhakara Y Babu, Kelli L. Boyd, Toru Takimoto, Allen Portner, Jonathan A. MccullersAbstract:An association exists between respiratory viruses and bacterial infections. Prevention or treatment of the preceding viral infection is a logical goal for reducing this important cause of morbidity and mortality. The ability of the novel, selective Parainfluenza virus hemagglutinin-neuraminidase inhibitor BCX 2798 to prevent the synergism between a paramyxovirus and Streptococcus pneumoniae was examined in this study. A model of secondary bacterial pneumonia after infection with a recombinant Sendai virus whose hemagglutinin-neuraminidase gene was replaced with that of human Parainfluenza virus type 1 [rSV(hHN)] was established in mice. Challenge of mice with a sublethal dose of S. pneumoniae 7 days after a sublethal infection with rSV(hHN) (synergistic group) caused 100% mortality. Bacterial infection preceding viral infection had no effect on survival. The mean bacterial titers in the synergistic group were significantly higher than in mice infected with bacteria only. The virus titers were similar in mice infected with rSV(hHN) alone and in dually infected mice. Intranasal administration of BCX 2798 at 10 mg/kg per day to the synergistic group of mice starting 4 h before virus infection protected 80% of animals from death. This effect was accompanied by a significant reduction in lung viral and bacterial titers. Treatment of mice 24 h after the rSV(hHN) infection showed no protection against synergistic lethality. Together, our results indicate that Parainfluenza viruses can prime for secondary bacterial infections. Prophylaxis of Parainfluenza virus infections with antivirals might be an effective strategy for prevention of secondary bacterial complications in humans.
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efficacy of novel hemagglutinin neuraminidase inhibitors bcx 2798 and bcx 2855 against human Parainfluenza viruses in vitro and in vivo
Antimicrobial Agents and Chemotherapy, 2004Co-Authors: Irina V Alymova, Sudhakara Y Babu, Chenghong Li, Xiaoping Xiong, Pooran Chand, Toru Takimoto, G. L. Taylor, Allen PortnerAbstract:Human Parainfluenza viruses are important respiratory tract pathogens, especially of children. However, no vaccines or specific therapies for infections caused by these viruses are currently available. In the present study we characterized the efficacy of the novel Parainfluenza virus inhibitors BCX 2798 and BCX 2855, which were designed based on the three-dimensional structure of the hemagglutinin-neuraminidase (HN) protein. The compounds were highly effective in inhibiting hemagglutinin (HA) and neuraminidase (NA) activities and the growth of hPIV-1, hPIV-2, and hPIV-3 in LLC-MK 2 cells. The concentrations required to reduce the activity to 50% of that of a control ranged from 0.1 to 6.0 μM in HA inhibition assays and from 0.02 to 20 μM in NA inhibition assays. The concentrations required to inhibit virus replication to 50% of the level of the control ranged from 0.7 to 11.5 μM. BCX 2798 and BCX 2855 were inactive against influenza virus HA and NA and bacterial NA. In mice infected with a recombinant Sendai virus whose HN gene was replaced with that of hPIV-1 [rSV(hHN)], intranasal administration of BCX 2798 (10 mg/kg per day) and of BCX 2855 (50 mg/kg per day) 4 h before the start of infection resulted in a significant reduction in titers of virus in the lungs and protection from death. Treatment beginning 24 h after the start of infection did not prevent death. Together, our results indicate that BCX 2798 and BCX 2855 are effective inhibitors of Parainfluenza virus HN and may limit Parainfluenza virus infections in humans.
Irina V Alymova - One of the best experts on this subject based on the ideXlab platform.
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the novel Parainfluenza virus hemagglutinin neuraminidase inhibitor bcx 2798 prevents lethal synergism between a paramyxovirus and streptococcus pneumoniae
Antimicrobial Agents and Chemotherapy, 2005Co-Authors: Irina V Alymova, Sudhakara Y Babu, Kelli L. Boyd, Toru Takimoto, Allen Portner, Jonathan A. MccullersAbstract:An association exists between respiratory viruses and bacterial infections. Prevention or treatment of the preceding viral infection is a logical goal for reducing this important cause of morbidity and mortality. The ability of the novel, selective Parainfluenza virus hemagglutinin-neuraminidase inhibitor BCX 2798 to prevent the synergism between a paramyxovirus and Streptococcus pneumoniae was examined in this study. A model of secondary bacterial pneumonia after infection with a recombinant Sendai virus whose hemagglutinin-neuraminidase gene was replaced with that of human Parainfluenza virus type 1 [rSV(hHN)] was established in mice. Challenge of mice with a sublethal dose of S. pneumoniae 7 days after a sublethal infection with rSV(hHN) (synergistic group) caused 100% mortality. Bacterial infection preceding viral infection had no effect on survival. The mean bacterial titers in the synergistic group were significantly higher than in mice infected with bacteria only. The virus titers were similar in mice infected with rSV(hHN) alone and in dually infected mice. Intranasal administration of BCX 2798 at 10 mg/kg per day to the synergistic group of mice starting 4 h before virus infection protected 80% of animals from death. This effect was accompanied by a significant reduction in lung viral and bacterial titers. Treatment of mice 24 h after the rSV(hHN) infection showed no protection against synergistic lethality. Together, our results indicate that Parainfluenza viruses can prime for secondary bacterial infections. Prophylaxis of Parainfluenza virus infections with antivirals might be an effective strategy for prevention of secondary bacterial complications in humans.
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efficacy of novel hemagglutinin neuraminidase inhibitors bcx 2798 and bcx 2855 against human Parainfluenza viruses in vitro and in vivo
Antimicrobial Agents and Chemotherapy, 2004Co-Authors: Irina V Alymova, Sudhakara Y Babu, Chenghong Li, Xiaoping Xiong, Pooran Chand, Toru Takimoto, G. L. Taylor, Allen PortnerAbstract:Human Parainfluenza viruses are important respiratory tract pathogens, especially of children. However, no vaccines or specific therapies for infections caused by these viruses are currently available. In the present study we characterized the efficacy of the novel Parainfluenza virus inhibitors BCX 2798 and BCX 2855, which were designed based on the three-dimensional structure of the hemagglutinin-neuraminidase (HN) protein. The compounds were highly effective in inhibiting hemagglutinin (HA) and neuraminidase (NA) activities and the growth of hPIV-1, hPIV-2, and hPIV-3 in LLC-MK 2 cells. The concentrations required to reduce the activity to 50% of that of a control ranged from 0.1 to 6.0 μM in HA inhibition assays and from 0.02 to 20 μM in NA inhibition assays. The concentrations required to inhibit virus replication to 50% of the level of the control ranged from 0.7 to 11.5 μM. BCX 2798 and BCX 2855 were inactive against influenza virus HA and NA and bacterial NA. In mice infected with a recombinant Sendai virus whose HN gene was replaced with that of hPIV-1 [rSV(hHN)], intranasal administration of BCX 2798 (10 mg/kg per day) and of BCX 2855 (50 mg/kg per day) 4 h before the start of infection resulted in a significant reduction in titers of virus in the lungs and protection from death. Treatment beginning 24 h after the start of infection did not prevent death. Together, our results indicate that BCX 2798 and BCX 2855 are effective inhibitors of Parainfluenza virus HN and may limit Parainfluenza virus infections in humans.
Sudhakara Y Babu - One of the best experts on this subject based on the ideXlab platform.
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the novel Parainfluenza virus hemagglutinin neuraminidase inhibitor bcx 2798 prevents lethal synergism between a paramyxovirus and streptococcus pneumoniae
Antimicrobial Agents and Chemotherapy, 2005Co-Authors: Irina V Alymova, Sudhakara Y Babu, Kelli L. Boyd, Toru Takimoto, Allen Portner, Jonathan A. MccullersAbstract:An association exists between respiratory viruses and bacterial infections. Prevention or treatment of the preceding viral infection is a logical goal for reducing this important cause of morbidity and mortality. The ability of the novel, selective Parainfluenza virus hemagglutinin-neuraminidase inhibitor BCX 2798 to prevent the synergism between a paramyxovirus and Streptococcus pneumoniae was examined in this study. A model of secondary bacterial pneumonia after infection with a recombinant Sendai virus whose hemagglutinin-neuraminidase gene was replaced with that of human Parainfluenza virus type 1 [rSV(hHN)] was established in mice. Challenge of mice with a sublethal dose of S. pneumoniae 7 days after a sublethal infection with rSV(hHN) (synergistic group) caused 100% mortality. Bacterial infection preceding viral infection had no effect on survival. The mean bacterial titers in the synergistic group were significantly higher than in mice infected with bacteria only. The virus titers were similar in mice infected with rSV(hHN) alone and in dually infected mice. Intranasal administration of BCX 2798 at 10 mg/kg per day to the synergistic group of mice starting 4 h before virus infection protected 80% of animals from death. This effect was accompanied by a significant reduction in lung viral and bacterial titers. Treatment of mice 24 h after the rSV(hHN) infection showed no protection against synergistic lethality. Together, our results indicate that Parainfluenza viruses can prime for secondary bacterial infections. Prophylaxis of Parainfluenza virus infections with antivirals might be an effective strategy for prevention of secondary bacterial complications in humans.
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efficacy of novel hemagglutinin neuraminidase inhibitors bcx 2798 and bcx 2855 against human Parainfluenza viruses in vitro and in vivo
Antimicrobial Agents and Chemotherapy, 2004Co-Authors: Irina V Alymova, Sudhakara Y Babu, Chenghong Li, Xiaoping Xiong, Pooran Chand, Toru Takimoto, G. L. Taylor, Allen PortnerAbstract:Human Parainfluenza viruses are important respiratory tract pathogens, especially of children. However, no vaccines or specific therapies for infections caused by these viruses are currently available. In the present study we characterized the efficacy of the novel Parainfluenza virus inhibitors BCX 2798 and BCX 2855, which were designed based on the three-dimensional structure of the hemagglutinin-neuraminidase (HN) protein. The compounds were highly effective in inhibiting hemagglutinin (HA) and neuraminidase (NA) activities and the growth of hPIV-1, hPIV-2, and hPIV-3 in LLC-MK 2 cells. The concentrations required to reduce the activity to 50% of that of a control ranged from 0.1 to 6.0 μM in HA inhibition assays and from 0.02 to 20 μM in NA inhibition assays. The concentrations required to inhibit virus replication to 50% of the level of the control ranged from 0.7 to 11.5 μM. BCX 2798 and BCX 2855 were inactive against influenza virus HA and NA and bacterial NA. In mice infected with a recombinant Sendai virus whose HN gene was replaced with that of hPIV-1 [rSV(hHN)], intranasal administration of BCX 2798 (10 mg/kg per day) and of BCX 2855 (50 mg/kg per day) 4 h before the start of infection resulted in a significant reduction in titers of virus in the lungs and protection from death. Treatment beginning 24 h after the start of infection did not prevent death. Together, our results indicate that BCX 2798 and BCX 2855 are effective inhibitors of Parainfluenza virus HN and may limit Parainfluenza virus infections in humans.
Anne Moscona - One of the best experts on this subject based on the ideXlab platform.
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structure guided improvement of a dual hpiv3 rsv fusion inhibitor
Journal of the American Chemical Society, 2020Co-Authors: Victor K Outlaw, Yun Zhu, Jennifer T Lemke, Samuel H Gellman, Matteo Porotto, Anne MosconaAbstract:Human Parainfluenza virus 3 (HPIV3) and respiratory syncytial virus (RSV) are leading causes of lower respiratory tract infections. There are currently no vaccines or antiviral therapeutics to trea...
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entry of Parainfluenza virus into cells as a target for interrupting childhood respiratory disease
Journal of Clinical Investigation, 2005Co-Authors: Anne MosconaAbstract:Human Parainfluenza viruses cause several serious respiratory diseases in children for which there is no effective prevention or therapy. Parainfluenza viruses initiate infection by binding to cell surface receptors and then, via coordinated action of the 2 viral surface glycoproteins, fuse directly with the cell membrane to release the viral replication machinery into the host cell’s cytoplasm. During this process, the receptor-binding molecule must trigger the viral fusion protein to mediate fusion and entry of the virus into a cell. This review explores the binding and entry into cells of Parainfluenza virus type 3, focusing on how the receptor-binding molecule triggers the fusion process. There are several steps during the process of binding, triggering, and fusion that are now understood at the molecular level, and each of these steps represents potential targets for interrupting infection.
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comparison of the virus receptor interactions of human Parainfluenza viruses types 1 2 and 3 995
Pediatric Research, 1996Co-Authors: Elizabeth Carlin, Kety Huberman, Collette Ahtye, Stephanie Schwartz, Anne MosconaAbstract:COMPARISON OF THE VIRUS-RECEPTOR INTERACTIONS OF HUMAN Parainfluenza VIRUSES TYPES 1, 2 and 3. † 995
