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NS1 protein as a novel anti-influenza target: Map-and-mutate antiviral rationale reveals new putative druggable hot spots with an important role on viral replication

2022-01-02Journal article Restricted access
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dc.contributor.authorTrigueiro-Louro, João
dc.contributor.authorSantos, Luís A.
dc.contributor.authorAlmeida, Filipe
dc.contributor.authorCorreia, Vanessa
dc.contributor.authorBrito, Rui M.M.
dc.contributor.authorRebelo-de-Andrade, Helena
dc.date.accessioned2023-03-20T11:22:27Z
dc.date.available2023-03-20T11:22:27Z
dc.date.issued2022-01-02
dc.description.abstractInfluenza NS1 is a promising anti-influenza target, considering its conserved and druggable structure, and key function in influenza replication and pathogenesis. Notwithstanding, target identification and validation, strengthened by experimental data, are lacking. Here, we further explored our previously designed structure-based antiviral rationale directed to highly conserved druggable NS1 regions across a broad spectrum of influenza A viruses. We aimed to identify NS1-mutated viruses exhibiting a reduced growth phenotype and/or an altered cell apoptosis profile. We found that NS1 mutations Y171A, K175A (consensus druggable pocket 1), W102A (consensus druggable pocket 3), Q121A and G184P (multiple consensus druggable pockets) - located at hot spots amenable for pharmacological modulation - significantly impaired A(H1N1)pdm09 virus replication, in vitro. This is the first time that NS1-K175A, -W102A, and -Q121A mutations are characterized. Our map-and-mutate strategy provides the basis to establish the NS1 as a promising target using a rationale with a higher resilience to resistance development.pt_PT
dc.description.abstractHighlights: Structure-based anti-influenza strategies that facilitate the rapid identification and validation of robust targets are lacking; We have previously identified and characterized 3 NS1 conserved druggable pockets - amenable to pharmacological modulation; NS1 mutations Y171A, K175A (CDP1), W102A (CDP3), Q121A and G184P (Multi-CDPs) impaired A(H1N1)pdm09 virus replication, in vitro; The new NS1 hot spots: NS1–K175, -W102, and -Q121 were characterized for the first time, using the A(H1N1)pdm09 virus; This map-and-mutate antiviral rationale can be promptly applied to other proteins of (re)emergent viruses.pt_PT
dc.description.sponsorshipThis work was funded by the FCT – Fundação para a Ciência e a Tecnologia, I.P. (project number POCI-01 0145-FEDER-032572 | PTDC/QUI-OUT/32572/2017 and PTDC/SAU-INF/30729/2017); and sup ported by the PhD grant PD/BD/128402/2017 from FCT PhD Pro gramme in Medicines and Pharmaceutical Innovation (i3DU) to JTL Ph. D. candidate.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationVirology. 2022 Jan 2;565:106-116. doi: 10.1016/j.virol.2021.11.001. Epub 2021 Nov 6.pt_PT
dc.identifier.doi10.1016/j.virol.2021.11.001pt_PT
dc.identifier.issn0042-6822
dc.identifier.urihttp://hdl.handle.net/10400.18/8564
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relationNovel antivirals against Influenza: NS1 target validation and lead discovery
dc.relationReverse Genetics Vaccine Seeds for Influenza: Mechanisms that drive the co-segregation of PB1 with antigenic proteins
dc.relationNS1 como alvo terapêutico emergente: na procura de novos fármacos contra o vírus influenza
dc.relation.publisherversionhttps://www.sciencedirect.com/science/article/pii/S0042682221002208?via%3Dihubpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subjectInfluenzapt_PT
dc.subjectInfluenza A Vruspt_PT
dc.subjectAntiviral Strategypt_PT
dc.subjectAntiviral Targetpt_PT
dc.subjectDruggable Pocketspt_PT
dc.subjectNS1pt_PT
dc.subjectViral Replicationpt_PT
dc.subjectInfecções Respiratóriaspt_PT
dc.subjectResistência aos Antimicrobianospt_PT
dc.titleNS1 protein as a novel anti-influenza target: Map-and-mutate antiviral rationale reveals new putative druggable hot spots with an important role on viral replicationpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleNovel antivirals against Influenza: NS1 target validation and lead discovery
oaire.awardTitleReverse Genetics Vaccine Seeds for Influenza: Mechanisms that drive the co-segregation of PB1 with antigenic proteins
oaire.awardTitleNS1 como alvo terapêutico emergente: na procura de novos fármacos contra o vírus influenza
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/9471 - RIDTI/PTDC%2FQUI-OUT%2F32572%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FSAU-INF%2F30729%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F128402%2F2017/PT
oaire.citation.endPage116pt_PT
oaire.citation.startPage106pt_PT
oaire.citation.titleVirologypt_PT
oaire.citation.volume565pt_PT
oaire.fundingStream9471 - RIDTI
oaire.fundingStream3599-PPCDT
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublication2c8b487c-89a0-444f-a168-fa07bedf802a
relation.isProjectOfPublicationa0e83cc0-de48-4e03-b202-2e61313186f5
relation.isProjectOfPublication7ea88733-a953-4463-97e1-5a85fe025637
relation.isProjectOfPublication.latestForDiscoverya0e83cc0-de48-4e03-b202-2e61313186f5

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