Efficacy of the New Neuraminidase Inhibitor CS-8958 against H5N1 Influenza Viruses

Maki Kiso,Shuku Kubo,Chairul A Nidom,Yoshihiro Kawaoka,Makoto Yamashita,Quynh Mai Le,Makoto Ozawa,Daniel R Perez

doi:10.1371/journal.ppat.1000786

Abstract

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.

Highlights

Human H1N1 and H3N2 influenza A viruses are highly contagious and cause ‘‘seasonal influenza’’ worldwide
Since the first human outbreak in Hong Kong in 1997, highly pathogenic H5N1 avian influenza A viruses have posed a threat to public health
We assessed the efficacy of CS-8958, a prodrug of the novel neuraminidase inhibitor R-125489, against highly pathogenic H5N1 influenza viruses in a murine lethal infection model

Summary

Introduction

Human H1N1 and H3N2 influenza A viruses are highly contagious and cause ‘‘seasonal influenza’’ worldwide. The emergence of a virus possessing hemagglutinin and neuraminidase (NA) to which humans have limited immunological memory creates the potential for ‘‘pandemic influenza’’. In 1997, human infections with highly pathogenic H5N1 avian influenza viruses were first documented in Hong Kong [3,4,5]. Since these viruses have spread throughout Asia, Europe, and Africa with high morbidity and mortality among avian species and with occasional transmission to humans with high mortality (http://www.who.int/csr/disease/ avian_influenza/en/). Human-to-human transmission is rare, once the H5N1 viruses acquire this ability, a devastating pandemic may be inevitable

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