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Novel Pandemic Influenza A(H1N1) Viruses Are Potently Inhibited by DAS181, a Sialidase Fusion Protein

BACKGROUND: The recent emergence of a novel pandemic influenza A(H1N1) strain in humans exemplifies the rapid and unpredictable nature of influenza virus evolution and the need for effective therapeutics and vaccines to control such outbreaks. However, resistance to antivirals can be a formidable pr...

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Autores principales: Triana-Baltzer, Gallen B., Gubareva, Larisa V., Nicholls, John M., Pearce, Melissa B., Mishin, Vasiliy P., Belser, Jessica A., Chen, Li-Mei, Chan, Renee W. Y., Chan, Michael C. W., Hedlund, Maria, Larson, Jeffrey L., Moss, Ronald B., Katz, Jacqueline M., Tumpey, Terrence M., Fang, Fang
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2770640/
https://www.ncbi.nlm.nih.gov/pubmed/19893747
http://dx.doi.org/10.1371/journal.pone.0007788
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author Triana-Baltzer, Gallen B.
Gubareva, Larisa V.
Nicholls, John M.
Pearce, Melissa B.
Mishin, Vasiliy P.
Belser, Jessica A.
Chen, Li-Mei
Chan, Renee W. Y.
Chan, Michael C. W.
Hedlund, Maria
Larson, Jeffrey L.
Moss, Ronald B.
Katz, Jacqueline M.
Tumpey, Terrence M.
Fang, Fang
author_facet Triana-Baltzer, Gallen B.
Gubareva, Larisa V.
Nicholls, John M.
Pearce, Melissa B.
Mishin, Vasiliy P.
Belser, Jessica A.
Chen, Li-Mei
Chan, Renee W. Y.
Chan, Michael C. W.
Hedlund, Maria
Larson, Jeffrey L.
Moss, Ronald B.
Katz, Jacqueline M.
Tumpey, Terrence M.
Fang, Fang
author_sort Triana-Baltzer, Gallen B.
collection PubMed
description BACKGROUND: The recent emergence of a novel pandemic influenza A(H1N1) strain in humans exemplifies the rapid and unpredictable nature of influenza virus evolution and the need for effective therapeutics and vaccines to control such outbreaks. However, resistance to antivirals can be a formidable problem as evidenced by the currently widespread oseltamivir- and adamantane-resistant seasonal influenza A viruses (IFV). Additional antiviral approaches with novel mechanisms of action are needed to combat novel and resistant influenza strains. DAS181 (Fludase™) is a sialidase fusion protein in early clinical development with in vitro and in vivo preclinical activity against a variety of seasonal influenza strains and highly pathogenic avian influenza strains (A/H5N1). Here, we use in vitro, ex vivo, and in vivo models to evaluate the activity of DAS181 against several pandemic influenza A(H1N1) viruses. METHODS AND FINDINGS: The activity of DAS181 against several pandemic influenza A(H1N1) virus isolates was examined in MDCK cells, differentiated primary human respiratory tract culture, ex-vivo human bronchi tissue and mice. DAS181 efficiently inhibited viral replication in each of these models and against all tested pandemic influenza A(H1N1) strains. DAS181 treatment also protected mice from pandemic influenza A(H1N1)-induced pathogenesis. Furthermore, DAS181 antiviral activity against pandemic influenza A(H1N1) strains was comparable to that observed against seasonal influenza virus including the H274Y oseltamivir-resistant influenza virus. CONCLUSIONS: The sialidase fusion protein DAS181 exhibits potent inhibitory activity against pandemic influenza A(H1N1) viruses. As inhibition was also observed with oseltamivir-resistant IFV (H274Y), DAS181 may be active against the antigenically novel pandemic influenza A(H1N1) virus should it acquire the H274Y mutation. Based on these and previous results demonstrating DAS181 broad-spectrum anti-IFV activity, DAS181 represents a potential therapeutic agent for prevention and treatment of infections by both emerging and seasonal strains of IFV.
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spelling pubmed-27706402009-11-06 Novel Pandemic Influenza A(H1N1) Viruses Are Potently Inhibited by DAS181, a Sialidase Fusion Protein Triana-Baltzer, Gallen B. Gubareva, Larisa V. Nicholls, John M. Pearce, Melissa B. Mishin, Vasiliy P. Belser, Jessica A. Chen, Li-Mei Chan, Renee W. Y. Chan, Michael C. W. Hedlund, Maria Larson, Jeffrey L. Moss, Ronald B. Katz, Jacqueline M. Tumpey, Terrence M. Fang, Fang PLoS One Research Article BACKGROUND: The recent emergence of a novel pandemic influenza A(H1N1) strain in humans exemplifies the rapid and unpredictable nature of influenza virus evolution and the need for effective therapeutics and vaccines to control such outbreaks. However, resistance to antivirals can be a formidable problem as evidenced by the currently widespread oseltamivir- and adamantane-resistant seasonal influenza A viruses (IFV). Additional antiviral approaches with novel mechanisms of action are needed to combat novel and resistant influenza strains. DAS181 (Fludase™) is a sialidase fusion protein in early clinical development with in vitro and in vivo preclinical activity against a variety of seasonal influenza strains and highly pathogenic avian influenza strains (A/H5N1). Here, we use in vitro, ex vivo, and in vivo models to evaluate the activity of DAS181 against several pandemic influenza A(H1N1) viruses. METHODS AND FINDINGS: The activity of DAS181 against several pandemic influenza A(H1N1) virus isolates was examined in MDCK cells, differentiated primary human respiratory tract culture, ex-vivo human bronchi tissue and mice. DAS181 efficiently inhibited viral replication in each of these models and against all tested pandemic influenza A(H1N1) strains. DAS181 treatment also protected mice from pandemic influenza A(H1N1)-induced pathogenesis. Furthermore, DAS181 antiviral activity against pandemic influenza A(H1N1) strains was comparable to that observed against seasonal influenza virus including the H274Y oseltamivir-resistant influenza virus. CONCLUSIONS: The sialidase fusion protein DAS181 exhibits potent inhibitory activity against pandemic influenza A(H1N1) viruses. As inhibition was also observed with oseltamivir-resistant IFV (H274Y), DAS181 may be active against the antigenically novel pandemic influenza A(H1N1) virus should it acquire the H274Y mutation. Based on these and previous results demonstrating DAS181 broad-spectrum anti-IFV activity, DAS181 represents a potential therapeutic agent for prevention and treatment of infections by both emerging and seasonal strains of IFV. Public Library of Science 2009-11-06 /pmc/articles/PMC2770640/ /pubmed/19893747 http://dx.doi.org/10.1371/journal.pone.0007788 Text en This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
spellingShingle Research Article
Triana-Baltzer, Gallen B.
Gubareva, Larisa V.
Nicholls, John M.
Pearce, Melissa B.
Mishin, Vasiliy P.
Belser, Jessica A.
Chen, Li-Mei
Chan, Renee W. Y.
Chan, Michael C. W.
Hedlund, Maria
Larson, Jeffrey L.
Moss, Ronald B.
Katz, Jacqueline M.
Tumpey, Terrence M.
Fang, Fang
Novel Pandemic Influenza A(H1N1) Viruses Are Potently Inhibited by DAS181, a Sialidase Fusion Protein
title Novel Pandemic Influenza A(H1N1) Viruses Are Potently Inhibited by DAS181, a Sialidase Fusion Protein
title_full Novel Pandemic Influenza A(H1N1) Viruses Are Potently Inhibited by DAS181, a Sialidase Fusion Protein
title_fullStr Novel Pandemic Influenza A(H1N1) Viruses Are Potently Inhibited by DAS181, a Sialidase Fusion Protein
title_full_unstemmed Novel Pandemic Influenza A(H1N1) Viruses Are Potently Inhibited by DAS181, a Sialidase Fusion Protein
title_short Novel Pandemic Influenza A(H1N1) Viruses Are Potently Inhibited by DAS181, a Sialidase Fusion Protein
title_sort novel pandemic influenza a(h1n1) viruses are potently inhibited by das181, a sialidase fusion protein
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2770640/
https://www.ncbi.nlm.nih.gov/pubmed/19893747
http://dx.doi.org/10.1371/journal.pone.0007788
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