Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, September 2009, p. 3942-3951, Vol. 53, No. 9
0066-4804/09/$08.00+0 doi:10.1128/AAC.00220-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Effect of Hemagglutinin-Neuraminidase Inhibitors BCX 2798 and BCX 2855 on Growth and Pathogenicity of Sendai/Human Parainfluenza Type 3 Chimera Virus in Mice
Makiko Watanabe,1
Vasiliy P. Mishin,1,
Scott A. Brown,2
Charles J. Russell,1
Kelli Boyd,4,
Y. Sudhakara Babu,5
Garry Taylor,6
Xiaoping Xiong,3
Xiaowei Yan,3
Allen Portner,1 and
Irina V. Alymova1*
Departments of Infectious Diseases,1 Immunology,2 Biostatistics,3 Animal Resource Center, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678,4 BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake Drive, Birmingham, Alabama 35244,5 Centre for Biomolecular Sciences, University of St. Andrews, North Haugh, St. Andrews, Fife KY16 9ST, Scotland6
Received 17 February 2009/ Returned for modification 2 April 2009/ Accepted 17 June 2009
Human parainfluenza virus type 3 (hPIV-3) is a major respiratory tract pathogen that affects young children, but no vaccines or antiviral drugs against it have yet been developed. We developed a mouse model to evaluate the efficacies of the novel parainfluenza virus hemagglutinin-neuraminidase (HN) inhibitors BCX 2798 and BCX 2855 against a recombinant Sendai virus (rSeV) in which the fusion (F) and HN surface glycoproteins (FHN) were replaced by those of hPIV-3 [rSeV(hPIV-3FHN)]. In the prophylaxis model, 129X1/SvJ mice were infected with a 90% or 20% lethal dose of the virus and were treated intranasally for 5 days with 10 mg/kg of body weight/day of either compound starting 4 h before infection. Prophylactic treatment of the mice with either compound did not prevent their death in a 90% lethality model of rSeV(hPIV-3FHN) infection. However, it significantly reduced the lung virus titers, the amount of weight lost, and the rate of mortality in mice infected with a 20% lethal virus dose. In the therapy model, mice were infected with a nonlethal dose of the virus (100 PFU/mouse) and were treated intranasally with 1 or 10 mg/kg/day of either compound for 5 days starting at 24 or 48 h postinfection. Treatment of the mice with either compound significantly reduced the virus titer in the lungs, subsequently causing a reduction in the number of immune cells and the levels of cytokines in the bronchoalveolar lavage fluid 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 the prophylaxis and treatment of hPIV-3 infection in humans.
* Corresponding author. Mailing address: Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678. Phone: (901) 595-3411. Fax: (901) 595-3099. E-mail: irina.alymova{at}stjude.org
Published ahead of print on 29 June 2009.
Present address: Virus Surveillance and Diagnosis Branch, Influenza Division, NCIRD, CCID, Centers for Disease Control and Prevention, 1600 Clifton Rd., Mail Stop G-16, Atlanta, GA 30333.
Present address: Department of Pathology, Division of Comparative Medicine, Vanderbilt University, 2201 West End Avenue, Nashville, TN 37240.
Antimicrobial Agents and Chemotherapy, September 2009, p. 3942-3951, Vol. 53, No. 9
0066-4804/09/$08.00+0 doi:10.1128/AAC.00220-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Copyright © 2009 by the American Society for Microbiology. For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»