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Article: Importance of neuraminidase active-site residues to the neuraminidase inhibitor resistance of influenza viruses

TitleImportance of neuraminidase active-site residues to the neuraminidase inhibitor resistance of influenza viruses
Authors
Issue Date2006
PublisherAmerican Society for Microbiology. The Journal's web site is located at http://jvi.asm.org/
Citation
Journal Of Virology, 2006, v. 80 n. 17, p. 8787-8795 How to Cite?
AbstractNeuraminidase inhibitors (NAIs) are antivirals designed to target conserved residues at the neuraminidase (NA) enzyme active site in influenza A and B viruses. The conserved residues that interact with NAIs are under selective pressure, but only a few have been linked to resistance. In the A/Wuhan/359/95 (H3N2) recombinant virus background, we characterized seven charged, conserved NA residues (R118, R371, E227, R152, R224, E276, and D151) that directly interact with the NAIs but have not been reported to confer resistance to NAIs. These NA residues were replaced with amino acids that possess side chains having similar properties to maintain their original charge. The NA mutations we introduced significantly decreased NA activity compared to that of the A/Wuhan/359/95 recombinant wild-type and R292K (an NA mutation frequently reported to confer resistance) viruses, which were analyzed for comparison. However, the recombinant viruses differed in replication efficiency when we serially passaged them in vitro; the growth of the R118K and E227D viruses was most impaired. The R224K, E276D, and R371K mutations conferred resistance to both zanamivir and oseltamivir, while the D151E mutation reduced susceptibility to oseltamivir only (∼ 10-fold) and the R152K mutation did not alter susceptibility to either drug. Because the R224K mutation was genetically unstable and the emergence of the R371K mutation in the N2 subtype is statistically unlikely, our results suggest that only the E276D mutation is likely to emerge under selective pressure. The results of our study may help to optimize the design of NAIs. Copyright © 2006, American Society for Microbiology. All Rights Reserved.
Persistent Identifierhttp://hdl.handle.net/10722/179795
ISSN
2015 Impact Factor: 4.606
2015 SCImago Journal Rankings: 3.347
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorYen, HLen_US
dc.contributor.authorHoffmann, Een_US
dc.contributor.authorTaylor, Gen_US
dc.contributor.authorScholtissek, Cen_US
dc.contributor.authorMonto, ASen_US
dc.contributor.authorWebster, RGen_US
dc.contributor.authorGovorkova, EAen_US
dc.date.accessioned2012-12-19T10:04:50Z-
dc.date.available2012-12-19T10:04:50Z-
dc.date.issued2006en_US
dc.identifier.citationJournal Of Virology, 2006, v. 80 n. 17, p. 8787-8795en_US
dc.identifier.issn0022-538Xen_US
dc.identifier.urihttp://hdl.handle.net/10722/179795-
dc.description.abstractNeuraminidase inhibitors (NAIs) are antivirals designed to target conserved residues at the neuraminidase (NA) enzyme active site in influenza A and B viruses. The conserved residues that interact with NAIs are under selective pressure, but only a few have been linked to resistance. In the A/Wuhan/359/95 (H3N2) recombinant virus background, we characterized seven charged, conserved NA residues (R118, R371, E227, R152, R224, E276, and D151) that directly interact with the NAIs but have not been reported to confer resistance to NAIs. These NA residues were replaced with amino acids that possess side chains having similar properties to maintain their original charge. The NA mutations we introduced significantly decreased NA activity compared to that of the A/Wuhan/359/95 recombinant wild-type and R292K (an NA mutation frequently reported to confer resistance) viruses, which were analyzed for comparison. However, the recombinant viruses differed in replication efficiency when we serially passaged them in vitro; the growth of the R118K and E227D viruses was most impaired. The R224K, E276D, and R371K mutations conferred resistance to both zanamivir and oseltamivir, while the D151E mutation reduced susceptibility to oseltamivir only (∼ 10-fold) and the R152K mutation did not alter susceptibility to either drug. Because the R224K mutation was genetically unstable and the emergence of the R371K mutation in the N2 subtype is statistically unlikely, our results suggest that only the E276D mutation is likely to emerge under selective pressure. The results of our study may help to optimize the design of NAIs. Copyright © 2006, American Society for Microbiology. All Rights Reserved.en_US
dc.languageengen_US
dc.publisherAmerican Society for Microbiology. The Journal's web site is located at http://jvi.asm.org/en_US
dc.relation.ispartofJournal of Virologyen_US
dc.subject.meshAnimalsen_US
dc.subject.meshAntiviral Agents - Pharmacologyen_US
dc.subject.meshBinding Sites - Geneticsen_US
dc.subject.meshCell Lineen_US
dc.subject.meshDrug Resistance, Viralen_US
dc.subject.meshHumansen_US
dc.subject.meshInfluenza A Virus, H3n2 Subtype - Drug Effects - Enzymology - Genetics - Physiologyen_US
dc.subject.meshMicrobial Sensitivity Tests - Methodsen_US
dc.subject.meshMutationen_US
dc.subject.meshNeuraminidase - Antagonists & Inhibitors - Chemistry - Metabolismen_US
dc.subject.meshRecombination, Geneticen_US
dc.subject.meshViral Plaque Assayen_US
dc.titleImportance of neuraminidase active-site residues to the neuraminidase inhibitor resistance of influenza virusesen_US
dc.typeArticleen_US
dc.identifier.emailYen, HL: hyen@hku.hken_US
dc.identifier.authorityYen, HL=rp00304en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1128/JVI.00477-06en_US
dc.identifier.pmid16912325-
dc.identifier.scopuseid_2-s2.0-33748645733en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33748645733&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume80en_US
dc.identifier.issue17en_US
dc.identifier.spage8787en_US
dc.identifier.epage8795en_US
dc.identifier.isiWOS:000239934500045-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridYen, HL=7102476668en_US
dc.identifier.scopusauthoridHoffmann, E=7201369718en_US
dc.identifier.scopusauthoridTaylor, G=7404202523en_US
dc.identifier.scopusauthoridScholtissek, C=7006002772en_US
dc.identifier.scopusauthoridMonto, AS=7004552306en_US
dc.identifier.scopusauthoridWebster, RG=36048363100en_US
dc.identifier.scopusauthoridGovorkova, EA=7003837718en_US

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