Efficacy of the novel parainfluenza virus haemagglutinin-neuraminidase inhibitor BCX 2798 in mice - further evaluation.
BACKGROUND
Human parainfluenza virus type 1 (hPIV-1) causes serious respiratory tract infections, especially in children. This study investigated the efficacy of the novel haemagglutinin-neuraminidase (HN) inhibitor BCX 2798 in the prophylaxis of lethal and the treatment of non-lethal parainfluenza virus infection in mice.


METHODS
In the prophylaxis model, 129x1/SvJ mice were inoculated with a 90% lethal dose of a recombinant Sendai virus, in which the HN gene was replaced with that of hPIV-1 (rSeV[hPIV-1HN]). The mice were intranasally treated either once or for 5 days with 1 or 10 mg/kg/day of BCX 2798, starting 4 h before infection. In the therapeutic model, mice were infected with 100 plaque-forming units of rSeV(hPIV-1HN) per mouse and treated intranasally with 0.1, 1 or 10 mg/kg/day of BCX 2798 for 5 days, starting 24 or 48 h after infection, or for 4 days starting 72 h after infection.


RESULTS
Similar to multiple dosing, a single intranasal prophylaxis with 1 or 10 mg/kg of BCX 2798 protected approximately 40% or 90%, respectively, of mice from death by rSeV(hPIV-1HN) infection. BCX 2798 also significantly reduced virus lung titres (in a dose- and time-dependent manner) and reduced histopathological changes in the airways of non-lethally infected mice at multiple intranasal dosages in the therapeutic model, with the lowest effective dosage being 0.1 mg/kg/day administered 24 h after infection.


CONCLUSIONS
BCX 2798 was effective in the prophylaxis of lethal and in the therapy of non-lethal parainfluenza virus infection in mice, suggesting further consideration of BCX 2798 for clinical trials.
Alymova
Irina V
IV
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA.
Watanabe
Makiko
M
Boyd
Kelli L
KL
Chand
Pooran
P
Babu
Y Sudhakara
YS
Portner
Allen
A
D000281:Administration, Intranasal; D000818:Animals; D001386:Azides / Q000008:administration & dosage* / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000378:metabolism; D005260:Female; D015707:HN Protein / Q000378:metabolism; D006603:Hexuronic Acids / Q000008:administration & dosage* / Q000378:metabolism; D006801:Humans; D008253:Macaca mulatta; D051379:Mice; D010222:Parainfluenza Virus 1, Human / Q000187:drug effects / Q000378:metabolism; D011292:Premedication; D010253:Respirovirus Infections / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D016896:Treatment Outcome
C486444:4-zido-5-isobutyrylamino-2,3-didehydro-2,3,4,5-tetradeoxyglycerogalacto-2-nonulopyranosic acid; D001386:Azides; D004791:Enzyme Inhibitors; D015707:HN Protein; D006603:Hexuronic Acids