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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...
Autores principales: | , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2829070/ https://www.ncbi.nlm.nih.gov/pubmed/20195462 http://dx.doi.org/10.1371/journal.ppat.1000786 |
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author | Kiso, Maki Kubo, Shuku Ozawa, Makoto Le, Quynh Mai Nidom, Chairul A. Yamashita, Makoto Kawaoka, Yoshihiro |
author_facet | Kiso, Maki Kubo, Shuku Ozawa, Makoto Le, Quynh Mai Nidom, Chairul A. Yamashita, Makoto Kawaoka, Yoshihiro |
author_sort | Kiso, Maki |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-2829070 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-28290702010-03-02 Efficacy of the New Neuraminidase Inhibitor CS-8958 against H5N1 Influenza Viruses Kiso, Maki Kubo, Shuku Ozawa, Makoto Le, Quynh Mai Nidom, Chairul A. Yamashita, Makoto Kawaoka, Yoshihiro PLoS Pathog Research Article 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. Public Library of Science 2010-02-26 /pmc/articles/PMC2829070/ /pubmed/20195462 http://dx.doi.org/10.1371/journal.ppat.1000786 Text en Kiso et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Kiso, Maki Kubo, Shuku Ozawa, Makoto Le, Quynh Mai Nidom, Chairul A. Yamashita, Makoto Kawaoka, Yoshihiro Efficacy of the New Neuraminidase Inhibitor CS-8958 against H5N1 Influenza Viruses |
title | Efficacy of the New Neuraminidase Inhibitor CS-8958 against H5N1 Influenza Viruses |
title_full | Efficacy of the New Neuraminidase Inhibitor CS-8958 against H5N1 Influenza Viruses |
title_fullStr | Efficacy of the New Neuraminidase Inhibitor CS-8958 against H5N1 Influenza Viruses |
title_full_unstemmed | Efficacy of the New Neuraminidase Inhibitor CS-8958 against H5N1 Influenza Viruses |
title_short | Efficacy of the New Neuraminidase Inhibitor CS-8958 against H5N1 Influenza Viruses |
title_sort | efficacy of the new neuraminidase inhibitor cs-8958 against h5n1 influenza viruses |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2829070/ https://www.ncbi.nlm.nih.gov/pubmed/20195462 http://dx.doi.org/10.1371/journal.ppat.1000786 |
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