Efficacy of the novel parainfluenza virus haemagglutinin-neuraminidase inhibitor BCX 2798 in mice - further evaluation

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. 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. 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. 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.