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Article: DAS181, a sialidase fusion protein, protects human airway epithelium against influenza virus infection: an in vitro pharmacodynamic analysis.

TitleDAS181, a sialidase fusion protein, protects human airway epithelium against influenza virus infection: an in vitro pharmacodynamic analysis.
Authors
KeywordsEx vivo bronchi
Fludase
HAE
Issue Date2010
Citation
The Journal Of Antimicrobial Chemotherapy, 2010, v. 65 n. 2, p. 275-284 How to Cite?
AbstractOBJECTIVES: The influenza virus (IFV) infection models commonly used to evaluate antiviral agents (e.g. MDCK cell line and mice) are limited by physiological differences from the human respiratory tract in vivo. Here we report the pharmacodynamics of DAS181, a sialidase fusion protein that inhibits influenza infection, in the model systems of well-defined human airway epithelium (HAE) culture and ex vivo culture of fresh human bronchial tissue, both of which are close mimics of the human respiratory tract in vivo. METHODS: HAE culture and ex vivo human bronchi were used to evaluate the sialic acid removal and regeneration efficiency and IFV inhibition after various DAS181 treatment levels and regimens. RESULTS: DAS181 effectively desialylates HAE cultures and ex vivo bronchi tissues and therefore potently inhibits replication of different IFV strains. The treatment effect of DAS181 occurs immediately upon application to the epithelial surface and is unaffected by the respiratory mucus. In both HAE and human bronchial tissue, the inhibitory effect of DAS181 treatment lasts for at least 2 days. Approximately 80% epithelial surface desialylation and significant anti-IFV efficacy can be achieved at topical concentrations of DAS181 in the range of 5-10 microg/cm(2) when applied once daily. An additional treatment or a higher loading dose of DAS181 on the first day provides significant additional treatment benefit. Comparing the effect of DAS181 versus its two analogues, DAS180 and DAS185, has confirmed that sialidase function is critical for DAS181, and the cell-binding domain (amphiregulin tag) prolongs DAS181 retention and potentiates its function. CONCLUSIONS: These results provide valuable insights into DAS181 treatment dose and potential regimens in the clinical setting.
Persistent Identifierhttp://hdl.handle.net/10722/146786
ISSN
2015 SCImago Journal Rankings: 2.157
ISI Accession Number ID
Funding AgencyGrant Number
National Institutes of Health/National Institute of Allergy and Infectious DiseasesU01AI070281
R44AI056786
HHSN266200600015C
Research Fund for the Control of Infectious Diseases08070842
Competitive Earmarked Research773507M
University Grants Committee of the Hong Kong Special Administrative Region, ChinaAoE/M-12/06
Funding Information:

The work at NexBio was supported in part by National Institutes of Health/National Institute of Allergy and Infectious Diseases (grant numbers U01AI070281 and R44AI056786, and contract number HHSN266200600015C). The work at the University of Hong Kong was supported by funding from: the Research Fund for the Control of Infectious Diseases (grant number 08070842); Competitive Earmarked Research Grants (grant number 773507M); and the Area of Excellence programme on Influenza supported by the University Grants Committee of the Hong Kong Special Administrative Region, China (Project number AoE/M-12/06).

Grants

 

DC FieldValueLanguage
dc.contributor.authorTrianaBaltzer, GBen_HK
dc.contributor.authorBabizki, Men_HK
dc.contributor.authorChan, MCen_HK
dc.contributor.authorWong, ACen_HK
dc.contributor.authorAschenbrenner, LMen_HK
dc.contributor.authorCampbell, ERen_HK
dc.contributor.authorLi, QXen_HK
dc.contributor.authorChan, RWen_HK
dc.contributor.authorPeiris, JSen_HK
dc.contributor.authorNicholls, JMen_HK
dc.contributor.authorFang, Fen_HK
dc.date.accessioned2012-05-10T09:16:07Z-
dc.date.available2012-05-10T09:16:07Z-
dc.date.issued2010en_HK
dc.identifier.citationThe Journal Of Antimicrobial Chemotherapy, 2010, v. 65 n. 2, p. 275-284en_HK
dc.identifier.issn1460-2091en_HK
dc.identifier.urihttp://hdl.handle.net/10722/146786-
dc.description.abstractOBJECTIVES: The influenza virus (IFV) infection models commonly used to evaluate antiviral agents (e.g. MDCK cell line and mice) are limited by physiological differences from the human respiratory tract in vivo. Here we report the pharmacodynamics of DAS181, a sialidase fusion protein that inhibits influenza infection, in the model systems of well-defined human airway epithelium (HAE) culture and ex vivo culture of fresh human bronchial tissue, both of which are close mimics of the human respiratory tract in vivo. METHODS: HAE culture and ex vivo human bronchi were used to evaluate the sialic acid removal and regeneration efficiency and IFV inhibition after various DAS181 treatment levels and regimens. RESULTS: DAS181 effectively desialylates HAE cultures and ex vivo bronchi tissues and therefore potently inhibits replication of different IFV strains. The treatment effect of DAS181 occurs immediately upon application to the epithelial surface and is unaffected by the respiratory mucus. In both HAE and human bronchial tissue, the inhibitory effect of DAS181 treatment lasts for at least 2 days. Approximately 80% epithelial surface desialylation and significant anti-IFV efficacy can be achieved at topical concentrations of DAS181 in the range of 5-10 microg/cm(2) when applied once daily. An additional treatment or a higher loading dose of DAS181 on the first day provides significant additional treatment benefit. Comparing the effect of DAS181 versus its two analogues, DAS180 and DAS185, has confirmed that sialidase function is critical for DAS181, and the cell-binding domain (amphiregulin tag) prolongs DAS181 retention and potentiates its function. CONCLUSIONS: These results provide valuable insights into DAS181 treatment dose and potential regimens in the clinical setting.en_HK
dc.languageengen_US
dc.relation.ispartofThe Journal of antimicrobial chemotherapyen_HK
dc.subjectEx vivo bronchien_HK
dc.subjectFludaseen_HK
dc.subjectHAEen_HK
dc.subject.meshAntiviral Agents - Pharmacokinetics - Pharmacologyen_US
dc.subject.meshCells, Cultureden_US
dc.subject.meshEpithelium - Virologyen_US
dc.subject.meshHumansen_US
dc.subject.meshInfluenza, Human - Prevention & Controlen_US
dc.subject.meshOrgan Culture Techniquesen_US
dc.subject.meshOrthomyxoviridae - Drug Effectsen_US
dc.subject.meshRecombinant Fusion Proteins - Pharmacokinetics - Pharmacologyen_US
dc.titleDAS181, a sialidase fusion protein, protects human airway epithelium against influenza virus infection: an in vitro pharmacodynamic analysis.en_HK
dc.typeArticleen_HK
dc.identifier.emailChan, MC: mchan@hku.hken_HK
dc.identifier.emailChan, RW: reneewy@hku.hken_HK
dc.identifier.emailPeiris, JS: malik@hkucc.hku.hken_HK
dc.identifier.emailNicholls, JM: jmnichol@hkucc.hku.hken_HK
dc.identifier.authorityChan, MC=rp00420en_HK
dc.identifier.authorityChan, RW=rp01596en_HK
dc.identifier.authorityPeiris, JS=rp00410en_HK
dc.identifier.authorityNicholls, JM=rp00364en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1093/jac/dkp421en_HK
dc.identifier.pmid19942616-
dc.identifier.scopuseid_2-s2.0-77950253495en_HK
dc.identifier.hkuros170670-
dc.identifier.volume65en_HK
dc.identifier.issue2en_HK
dc.identifier.spage275en_HK
dc.identifier.epage284en_HK
dc.identifier.eissn0305-7453-
dc.identifier.isiWOS:000273892600017-
dc.relation.projectSusceptibility of the upper respiratory tract to influenza virus infection following desialyation-
dc.relation.projectControl of Pandemic and Inter-pandemic Influenza-
dc.identifier.scopusauthoridTrianaBaltzer, GB=6504655978en_HK
dc.identifier.scopusauthoridBabizki, M=35748404700en_HK
dc.identifier.scopusauthoridChan, MC=26654715500en_HK
dc.identifier.scopusauthoridWong, AC=35749351000en_HK
dc.identifier.scopusauthoridAschenbrenner, LM=6506505198en_HK
dc.identifier.scopusauthoridCampbell, ER=12808429000en_HK
dc.identifier.scopusauthoridLi, QX=35748971500en_HK
dc.identifier.scopusauthoridChan, RW=26661379100en_HK
dc.identifier.scopusauthoridPeiris, JS=7005486823en_HK
dc.identifier.scopusauthoridNicholls, JM=7201463077en_HK
dc.identifier.scopusauthoridFang, F=7202929817en_HK

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