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Mutations in the chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broad-spectrum antiviral

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dc.creatorDelang, Leenspa
dc.creatorGuerrero, Nidya Seguraspa
dc.creatorTas, Alispa
dc.creatorQuérat, Gillesspa
dc.creatorPastorino, Borisspa
dc.creatorFroeyen, Mathyspa
dc.creatorDallmeier, Kaispa
dc.creatorJochmans, Dirkspa
dc.creatorHerdewijn, Pietspa
dc.creatorBello, Feliospa
dc.creatorSnijder, Eric J.spa
dc.creatorde Lamballerie, Xavierspa
dc.creatorMartina, Byronspa
dc.creatorNeyts, Johanspa
dc.creatorvan Hemert, Martijn J.spa
dc.creatorLeyssen, Pieterspa
dc.date.accessioned2020-05-25T23:55:49Z
dc.date.available2020-05-25T23:55:49Z
dc.date.created2014spa
dc.description.abstractObjectives: T-705, also known as favipiravir, is a small-molecule inhibitor that is currently in clinical development for the treatment of influenza virus infections. This molecule also inhibits the replication of a broad spectrum of other RNA viruses. The objective of this study was to investigate the antiviral effect of favipiravir on chikungunya virus (CHIKV) replication and to contribute to unravelling the molecular mechanism of action against this virus. Methods: The anti-CHIKV effect of favipiravir was examined in cell culture and in a mouse model of lethal infection. A five-step protocol was used to select for CHIKV variants with reduced susceptibility to favipiravir. The resistant phenotype was confirmed in cell culture and the whole genome was sequenced. The identified mutations were reverse-engineered into an infectious clone to confirm their impact on the antiviral efficacy of favipiravir. Results: Favipiravir inhibits the replication of laboratory strains and clinical isolates of CHIKV, as well as of a panel of other alphaviruses. Several favipiravir-resistant CHIKV variants were independently selected and all of them in particular acquired the unique K291R mutation in the RNA-dependent RNA polymerase (RdRp). Reverse-engineering of this K291R mutation into an infectious clone of CHIKV confirmed the link between the mutant genotype and the resistant phenotype. Interestingly, this particular lysine is also highly conserved in the RdRp of positivestranded RNA viruses in general. Conclusions: This study provides an important insight into the precise molecular mechanism by which favipiravir exerts its antiviral activity against (alpha)viruses, which may be of help in designing other potent broad-spectrum antivirals.eng
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1093/jac/dku209
dc.identifier.issn03057453
dc.identifier.issn14602091
dc.identifier.urihttps://repository.urosario.edu.co/handle/10336/22227
dc.language.isoengspa
dc.publisherOxford University Pressspa
dc.relation.citationEndPage2784
dc.relation.citationIssueNo. 10
dc.relation.citationStartPage2770
dc.relation.citationTitleJournal of Antimicrobial Chemotherapy
dc.relation.citationVolumeVol. 69
dc.relation.ispartofJournal of Antimicrobial Chemotherapy, ISSN:03057453, 14602091, Vol.69, No.10 (2014); pp. 2770-2784spa
dc.relation.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-84925406921&doi=10.1093%2fjac%2fdku209&partnerID=40&md5=43dca39f60798fe1473375266b366118spa
dc.rights.accesRightsinfo:eu-repo/semantics/openAccess
dc.rights.accesoAbierto (Texto Completo)spa
dc.source.instnameinstname:Universidad del Rosariospa
dc.source.reponamereponame:Repositorio Institucional EdocURspa
dc.subject.keywordAntivirus agentspa
dc.subject.keywordanimaleng
dc.subject.keywordFavipiravirspa
dc.subject.keywordLysinespa
dc.subject.keywordNonstructural proteinspa
dc.subject.keywordRna directed rna polymerasespa
dc.subject.keywordT 1005spa
dc.subject.keywordUnclassified drugspa
dc.subject.keywordViral proteinspa
dc.subject.keywordAmidespa
dc.subject.keywordAntivirus agentspa
dc.subject.keywordFavipiravirspa
dc.subject.keywordPyrazine derivativespa
dc.subject.keywordVirus proteinspa
dc.subject.keywordAlphavirusspa
dc.subject.keywordAnimal cellspa
dc.subject.keywordAnimal experimentspa
dc.subject.keywordAnimal modelspa
dc.subject.keywordAntiviral activityspa
dc.subject.keywordArticlespa
dc.subject.keywordBarmah forest virusspa
dc.subject.keywordChikungunyaspa
dc.subject.keywordChikungunya virusspa
dc.subject.keywordControlled studyspa
dc.subject.keywordDrug efficacyspa
dc.subject.keywordEastern equine encephalitis virusspa
dc.subject.keywordEc50spa
dc.subject.keywordGenotypespa
dc.subject.keywordMousespa
dc.subject.keywordMutationspa
dc.subject.keywordNonhumanspa
dc.subject.keywordO nyong nyong virusspa
dc.subject.keywordPhenotypespa
dc.subject.keywordReverse engineeringspa
dc.subject.keywordRoss river virusspa
dc.subject.keywordSemliki forest virusspa
dc.subject.keywordSindbis virusspa
dc.subject.keywordVenezuelan equine encephalitis virusspa
dc.subject.keywordVirus cell interactionspa
dc.subject.keywordVirus genomespa
dc.subject.keywordVirus infectivityspa
dc.subject.keywordVirus isolationspa
dc.subject.keywordVirus loadspa
dc.subject.keywordVirus replicationspa
dc.subject.keywordVirus strainspa
dc.subject.keywordAnimalspa
dc.subject.keywordAntiviral resistancespa
dc.subject.keywordCell linespa
dc.subject.keywordChemistryspa
dc.subject.keywordChikungunya feverspa
dc.subject.keywordChikungunya virusspa
dc.subject.keywordCytopathogenic effectspa
dc.subject.keywordDisease modelspa
dc.subject.keywordDose responsespa
dc.subject.keywordDrug effectsspa
dc.subject.keywordGeneticsspa
dc.subject.keywordMicrobial sensitivity testspa
dc.subject.keywordReproducibilityspa
dc.subject.keywordVirologyspa
dc.subject.keywordAmidesspa
dc.subject.keywordAnimalsspa
dc.subject.keywordAntiviral agentsspa
dc.subject.keywordCell linespa
dc.subject.keywordChikungunya feverspa
dc.subject.keywordChikungunya virusspa
dc.subject.keywordCytopathogenic effecteng
dc.subject.keywordDisease modelseng
dc.subject.keywordDose-response relationshipeng
dc.subject.keywordDrug resistanceeng
dc.subject.keywordMicespa
dc.subject.keywordMicrobial sensitivity testsspa
dc.subject.keywordMutationspa
dc.subject.keywordPhenotypespa
dc.subject.keywordPyrazinesspa
dc.subject.keywordReproducibility of resultsspa
dc.subject.keywordViral nonstructural proteinsspa
dc.subject.keywordVirus replicationspa
dc.subject.keywordAlphavirusspa
dc.subject.keywordNsp4spa
dc.subject.keywordPolymerasespa
dc.titleMutations in the chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broad-spectrum antiviralspa
dc.typearticleeng
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersion
dc.type.spaArtículospa
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