Efficacy of the new neuraminidase inhibitor CS-8958 against H5N1 influenza viruses

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 μg/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. © 2010 kiso et al.