Giuseppe
Emeritus
Antimicrob Agents Chemother. 2009 Jun 29. [Epub ahead of print]
Effect of Hemagglutinin-Neuraminidase Inhibitors BCX 2798 and BCX 2855 on Growth and Pathogenicity of Sendai/Human Parainfluenza Type 3 Chimera Virus in Mice.
Watanabe M, Mishin VP, Brown SA, Russell CJ, Boyd K, Babu YS, Taylor G, Xiong X, Yan X, Portner A, Alymova IV.
Departments of Infectious Diseases, Immunology, Biostatistics, and Animal Resource Center, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678, USA; BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake Drive, Birmingham, AL 35244, USA; Center for Biomolecular Science, University of St. Andrews, North Haugh, St. Andrews, Fife KY16 9ST, Scotland.
Human parainfluenza virus type 3 (hPIV-3) is a major respiratory tract pathogen affecting young children, but no vaccines or antiviral drugs have yet been developed against it. We developed a mouse model to evaluate the efficacy of the novel parainfluenza virus hemagglutinin-neuraminidase (HN) inhibitors BCX 2798 and BCX 2855 against a recombinant Sendai virus in which the fusion and HN surface glycoproteins were substituted with those of hPIV-3 (rSeV[hPIV-3FHN]). In the prophylactic model, 129x1/SvJ mice were infected with a 90% or 20% lethal dose of the virus and treated intranasally for 5 days with 10 mg/kg/day of either compound, starting 4 h before infection. Prophylactic treatment of mice with either compound did not prevent their death in a 90% lethal model of rSeV(hPIV-3FHN) infection. However, it significantly reduced virus lung titers, weight loss, and mortality in mice infected with a 20% lethal virus dose. In the therapeutic model, mice were infected with a nonlethal dose of the virus (100 PFU/mouse) and treated intranasally with 1 or 10 mg/kg/day of either compound for 5 days, starting 24 or 48 h postinfection. Treatment of mice with either compound significantly reduced virus titer in the lungs, subsequently causing a reduction in the number of immune cells and level of cytokines in the bronchoalveolar lavage, and histopathologic changes in the airways. Our results indicate that BCX 2798 and BCX 2855 are effective inhibitors of hPIV-3 HN in our mouse model and may be promising candidates for prophylaxis and treatment of hPIV-3 infection in humans.
PMID: 19564364 [PubMed - as supplied by publisher]
-
------
Effect of Hemagglutinin-Neuraminidase Inhibitors BCX 2798 and BCX 2855 on Growth and Pathogenicity of Sendai/Human Parainfluenza Type 3 Chimera Virus in Mice.
Watanabe M, Mishin VP, Brown SA, Russell CJ, Boyd K, Babu YS, Taylor G, Xiong X, Yan X, Portner A, Alymova IV.
Departments of Infectious Diseases, Immunology, Biostatistics, and Animal Resource Center, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678, USA; BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake Drive, Birmingham, AL 35244, USA; Center for Biomolecular Science, University of St. Andrews, North Haugh, St. Andrews, Fife KY16 9ST, Scotland.
Human parainfluenza virus type 3 (hPIV-3) is a major respiratory tract pathogen affecting young children, but no vaccines or antiviral drugs have yet been developed against it. We developed a mouse model to evaluate the efficacy of the novel parainfluenza virus hemagglutinin-neuraminidase (HN) inhibitors BCX 2798 and BCX 2855 against a recombinant Sendai virus in which the fusion and HN surface glycoproteins were substituted with those of hPIV-3 (rSeV[hPIV-3FHN]). In the prophylactic model, 129x1/SvJ mice were infected with a 90% or 20% lethal dose of the virus and treated intranasally for 5 days with 10 mg/kg/day of either compound, starting 4 h before infection. Prophylactic treatment of mice with either compound did not prevent their death in a 90% lethal model of rSeV(hPIV-3FHN) infection. However, it significantly reduced virus lung titers, weight loss, and mortality in mice infected with a 20% lethal virus dose. In the therapeutic model, mice were infected with a nonlethal dose of the virus (100 PFU/mouse) and treated intranasally with 1 or 10 mg/kg/day of either compound for 5 days, starting 24 or 48 h postinfection. Treatment of mice with either compound significantly reduced virus titer in the lungs, subsequently causing a reduction in the number of immune cells and level of cytokines in the bronchoalveolar lavage, and histopathologic changes in the airways. Our results indicate that BCX 2798 and BCX 2855 are effective inhibitors of hPIV-3 HN in our mouse model and may be promising candidates for prophylaxis and treatment of hPIV-3 infection in humans.
PMID: 19564364 [PubMed - as supplied by publisher]
-
------