Eeyarestatin I, an inhibitor of the valosin-containing protein, exhibits potent virucidal activity against the flaviviruses

Cellular responses to stress generally lead to the activation of the endoplasmic reticulum-associated protein degradation (ERAD) pathway. Several lines of study support that ERAD may be playing a proviral role during flaviviral infection. A key host factor in ERAD is the valosin-containing protein (...

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Detalles Bibliográficos
Autores: Rodrigo, Imanol, Ballesta, Carlos, Nunes, Eliane Blanco, Pérez, Patricia, García-Arriaza, Juan, Arias, Armando
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/422461
Acceso en línea:http://hdl.handle.net/10261/422461
https://api.elsevier.com/content/abstract/scopus_id/85138581496
Access Level:acceso abierto
Palabra clave:ER-derived membrane
ERAD
Eeyarestatin I
Enveloped viruses
Usutu
Virucide
Zika
http://metadata.un.org/sdg/3
Ensure healthy lives and promote well-being for all at all ages
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spelling Eeyarestatin I, an inhibitor of the valosin-containing protein, exhibits potent virucidal activity against the flavivirusesRodrigo, ImanolBallesta, CarlosNunes, Eliane BlancoPérez, PatriciaGarcía-Arriaza, JuanArias, ArmandoER-derived membraneERADEeyarestatin IEnveloped virusesUsutuVirucideZikahttp://metadata.un.org/sdg/3Ensure healthy lives and promote well-being for all at all agesCellular responses to stress generally lead to the activation of the endoplasmic reticulum-associated protein degradation (ERAD) pathway. Several lines of study support that ERAD may be playing a proviral role during flaviviral infection. A key host factor in ERAD is the valosin-containing protein (VCP), an ATPase which ushers ubiquitin-tagged proteins to degradation by the proteasome. VCP exhibits different proviral activities, such as engaging in the biogenesis of viral replication organelles and facilitating flavivirus genome uncoating after the viral particle entry. To investigate the possible antiviral value of drugs targeting VCP, we tested two inhibitors: eeyarestatin I (EEY) and xanthohumol (XAN). Both compounds were highly effective in suppressing Zika virus (ZIKV) and Usutu virus (USUV) replication during infection in cell culture. Further analysis revealed an unexpected virucidal activity for EEY, but not for XAN. Preincubation of ZIKV or USUV with EEY before inoculation to cells resulted in significant decreases in infectivity in a dose- and time-dependent manner. Viral genomes in samples previously treated with EEY were more sensitive to propidium monoazide, an intercalating agent, with 10- to 100-fold decreases observed in viral RNA levels, supporting that EEY affects viral particle integrity. Altogether, these results support that EEY is a strong virucide against two unrelated flaviviruses, encouraging further studies to investigate its potential use as a broad-acting drug or the development of improved derivatives in the treatment of flaviviral infection.This research was funded by Ministerio de Ciencia, Innovación y Universidades (MICIU) of Spain, grant number PID2019-106068 GB-I00, and by Junta de Comunidades de Castilla-La Mancha, grant number SBPLY/21/180501/000076. Part of this research was also funded by Fondo Supera COVID-19 grant (Crue Universidades-Banco Santander), Spanish Research Council (CSIC) grant 202120E079, and Spanish Ministry of Science and Innovation (MCIN)/Spanish Research Agency (AEI)/10.13039/501100011033 grant PID2020-114481RB-I00 to JG-A. AA is the recipient of a Beatriz Galindo Senior Fellowship (BEAGAL18/00074) from MICIU. IR has been supported by a predoctoral fellowship (2020-PREDUCLM-16723) and CB by a Beca CRIB Iniciación 2021 (BII2021/01), both granted by UCLM.Peer reviewedSin uso de modelos vivosElsevierMinisterio de Ciencia e Innovación (España)Junta de Comunidades de Castilla-La ManchaBanco SantanderGarcía-Arriaza, Juan [0000-0002-5167-5724]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202620262022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/422461https://api.elsevier.com/content/abstract/scopus_id/85138581496reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-106068GB-I00SBPLY/21/180501/000076info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-114481RB-I00Antiviral researchapplication/pdfhttps://doi.org/10.1016/j.antiviral.2022.105416Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/4224612026-05-22T06:33:51Z
dc.title.none.fl_str_mv Eeyarestatin I, an inhibitor of the valosin-containing protein, exhibits potent virucidal activity against the flaviviruses
title Eeyarestatin I, an inhibitor of the valosin-containing protein, exhibits potent virucidal activity against the flaviviruses
spellingShingle Eeyarestatin I, an inhibitor of the valosin-containing protein, exhibits potent virucidal activity against the flaviviruses
Rodrigo, Imanol
ER-derived membrane
ERAD
Eeyarestatin I
Enveloped viruses
Usutu
Virucide
Zika
http://metadata.un.org/sdg/3
Ensure healthy lives and promote well-being for all at all ages
title_short Eeyarestatin I, an inhibitor of the valosin-containing protein, exhibits potent virucidal activity against the flaviviruses
title_full Eeyarestatin I, an inhibitor of the valosin-containing protein, exhibits potent virucidal activity against the flaviviruses
title_fullStr Eeyarestatin I, an inhibitor of the valosin-containing protein, exhibits potent virucidal activity against the flaviviruses
title_full_unstemmed Eeyarestatin I, an inhibitor of the valosin-containing protein, exhibits potent virucidal activity against the flaviviruses
title_sort Eeyarestatin I, an inhibitor of the valosin-containing protein, exhibits potent virucidal activity against the flaviviruses
dc.creator.none.fl_str_mv Rodrigo, Imanol
Ballesta, Carlos
Nunes, Eliane Blanco
Pérez, Patricia
García-Arriaza, Juan
Arias, Armando
author Rodrigo, Imanol
author_facet Rodrigo, Imanol
Ballesta, Carlos
Nunes, Eliane Blanco
Pérez, Patricia
García-Arriaza, Juan
Arias, Armando
author_role author
author2 Ballesta, Carlos
Nunes, Eliane Blanco
Pérez, Patricia
García-Arriaza, Juan
Arias, Armando
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia e Innovación (España)
Junta de Comunidades de Castilla-La Mancha
Banco Santander
García-Arriaza, Juan [0000-0002-5167-5724]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv ER-derived membrane
ERAD
Eeyarestatin I
Enveloped viruses
Usutu
Virucide
Zika
http://metadata.un.org/sdg/3
Ensure healthy lives and promote well-being for all at all ages
topic ER-derived membrane
ERAD
Eeyarestatin I
Enveloped viruses
Usutu
Virucide
Zika
http://metadata.un.org/sdg/3
Ensure healthy lives and promote well-being for all at all ages
description Cellular responses to stress generally lead to the activation of the endoplasmic reticulum-associated protein degradation (ERAD) pathway. Several lines of study support that ERAD may be playing a proviral role during flaviviral infection. A key host factor in ERAD is the valosin-containing protein (VCP), an ATPase which ushers ubiquitin-tagged proteins to degradation by the proteasome. VCP exhibits different proviral activities, such as engaging in the biogenesis of viral replication organelles and facilitating flavivirus genome uncoating after the viral particle entry. To investigate the possible antiviral value of drugs targeting VCP, we tested two inhibitors: eeyarestatin I (EEY) and xanthohumol (XAN). Both compounds were highly effective in suppressing Zika virus (ZIKV) and Usutu virus (USUV) replication during infection in cell culture. Further analysis revealed an unexpected virucidal activity for EEY, but not for XAN. Preincubation of ZIKV or USUV with EEY before inoculation to cells resulted in significant decreases in infectivity in a dose- and time-dependent manner. Viral genomes in samples previously treated with EEY were more sensitive to propidium monoazide, an intercalating agent, with 10- to 100-fold decreases observed in viral RNA levels, supporting that EEY affects viral particle integrity. Altogether, these results support that EEY is a strong virucide against two unrelated flaviviruses, encouraging further studies to investigate its potential use as a broad-acting drug or the development of improved derivatives in the treatment of flaviviral infection.
publishDate 2022
dc.date.none.fl_str_mv 2022
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/422461
https://api.elsevier.com/content/abstract/scopus_id/85138581496
url http://hdl.handle.net/10261/422461
https://api.elsevier.com/content/abstract/scopus_id/85138581496
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-106068GB-I00
SBPLY/21/180501/000076
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-114481RB-I00
Antiviral research
application/pdf
https://doi.org/10.1016/j.antiviral.2022.105416
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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