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

Detalhes bibliográficos
Autor(a) principal: Trigueiro-Louro, João
Data de Publicação: 2022
Outros Autores: Santos, Luís A., Almeida, Filipe, Correia, Vanessa, Brito, Rui M.M., Rebelo-de-Andrade, Helena
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10400.18/8564
Resumo: Influenza 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.
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spelling 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 replicationInfluenzaInfluenza A VrusAntiviral StrategyAntiviral TargetDruggable PocketsNS1Viral ReplicationInfecções RespiratóriasResistência aos AntimicrobianosInfluenza 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.Highlights: 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.This 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.ElsevierRepositório Científico do Instituto Nacional de SaúdeTrigueiro-Louro, JoãoSantos, Luís A.Almeida, FilipeCorreia, VanessaBrito, Rui M.M.Rebelo-de-Andrade, Helena2023-03-20T11:22:27Z2022-01-022022-01-02T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.18/8564engVirology. 2022 Jan 2;565:106-116. doi: 10.1016/j.virol.2021.11.001. Epub 2021 Nov 6.0042-682210.1016/j.virol.2021.11.001info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-20T15:42:38Zoai:repositorio.insa.pt:10400.18/8564Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:43:12.394881Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv 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
title 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
spellingShingle 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
Trigueiro-Louro, João
Influenza
Influenza A Vrus
Antiviral Strategy
Antiviral Target
Druggable Pockets
NS1
Viral Replication
Infecções Respiratórias
Resistência aos Antimicrobianos
title_short 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_sort 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
author Trigueiro-Louro, João
author_facet Trigueiro-Louro, João
Santos, Luís A.
Almeida, Filipe
Correia, Vanessa
Brito, Rui M.M.
Rebelo-de-Andrade, Helena
author_role author
author2 Santos, Luís A.
Almeida, Filipe
Correia, Vanessa
Brito, Rui M.M.
Rebelo-de-Andrade, Helena
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório Científico do Instituto Nacional de Saúde
dc.contributor.author.fl_str_mv Trigueiro-Louro, João
Santos, Luís A.
Almeida, Filipe
Correia, Vanessa
Brito, Rui M.M.
Rebelo-de-Andrade, Helena
dc.subject.por.fl_str_mv Influenza
Influenza A Vrus
Antiviral Strategy
Antiviral Target
Druggable Pockets
NS1
Viral Replication
Infecções Respiratórias
Resistência aos Antimicrobianos
topic Influenza
Influenza A Vrus
Antiviral Strategy
Antiviral Target
Druggable Pockets
NS1
Viral Replication
Infecções Respiratórias
Resistência aos Antimicrobianos
description Influenza 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.
publishDate 2022
dc.date.none.fl_str_mv 2022-01-02
2022-01-02T00:00:00Z
2023-03-20T11:22:27Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10400.18/8564
url http://hdl.handle.net/10400.18/8564
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Virology. 2022 Jan 2;565:106-116. doi: 10.1016/j.virol.2021.11.001. Epub 2021 Nov 6.
0042-6822
10.1016/j.virol.2021.11.001
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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