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

PLoS Pathogens

Shuku Kubo¹  Yoshihiro Kawaoka¹  Quynh Mai Le²  Maki Kiso³  Makoto Yamashita⁴  Makoto Ozawa⁵  Chairul A. Nidom⁶ 

[1] Biological Research Laboratories, Daiichi Sankyo Co. Ltd., Hiromachi, Shinagawa-ku, Tokyo, Japan;Department of Pathobiological Sciences, University of Wisconsin, Madison, Wisconsin, United States of America;Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan;Faculty of Veterinary Medicine, Tropical Disease Centre, Airlangga University, Surabaya, Indonesia;International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan;National Institute of Hygiene and Epidemiology, Hanoi, Vietnam

关键词: H5N1;    Influenza viruses;    Phosphates;    H1N1;    Influenza;    Influenza A virus;    Prophylaxis;    Viral pathogens;   

DOI  :  10.1371/journal.ppat.1000786

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY