Currently, two
neuraminidase (NA) inhibitors,
oseltamivir and
zanamivir, which must be administrated twice daily for 5 days for maximum
therapeutic effect, are licensed for the treatment of
influenza. However,
oseltamivir-resistant mutants of seasonal H1N1 and highly pathogenic H5N1
avian influenza A viruses have emerged. Therefore, alternative
antiviral agents are needed. Recently, a new
neuraminidase inhibitor,
R-125489, and its
prodrug,
CS-8958, have been developed.
CS-8958 functions as a long-acting NA inhibitor in vivo (mice) and is efficacious against seasonal
influenza strains following a single intranasal dose. Here, we tested the efficacy of this compound against H5N1 influenza viruses, which have spread across several continents and caused epidemics with high morbidity and mortality. We demonstrated that
R-125489 interferes with the NA activity of H5N1 viruses, including
oseltamivir-resistant and different clade strains. A single dose of
CS-8958 (1,500 microg/kg) given to mice 2 h post-
infection with H5N1 influenza viruses produced a higher survival rate than did continuous five-day administration of
oseltamivir (50 mg/kg twice daily). Virus titers in lungs and brain were substantially lower in infected mice treated with a single dose of
CS-8958 than in those treated with the five-day course of
oseltamivir.
CS-8958 was also highly efficacious against highly pathogenic H5N1 influenza virus and
oseltamivir-resistant variants. A single dose of
CS-8958 given seven days prior to
virus infection also protected mice against H5N1 virus lethal
infection. To evaluate the improved efficacy of
CS-8958 over
oseltamivir, the binding stability of
R-125489 to various subtypes of influenza virus was assessed and compared with that of other NA inhibitors. We found that
R-125489 bound to NA more tightly than did any other NA inhibitor tested. Our results indicate that
CS-8958 is highly effective for the treatment and prophylaxis of
infection with H5N1 influenza viruses, including
oseltamivir-resistant mutants.