Proteomic Discovery of VEEV E2-Host Partner Interactions Identifies GRP78 Inhibitor HA15 as a Potential Therapeutic for Alphavirus Infections

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dc.contributor.authorBarrera, Michael D.en
dc.contributor.authorCallahan, Victoriaen
dc.contributor.authorAkhrymuk, Ivan V.en
dc.contributor.authorBhalla, Nishanken
dc.contributor.authorZhou, Weidongen
dc.contributor.authorCampbell, Catherineen
dc.contributor.authorNarayanan, Aarthien
dc.contributor.authorKehn-Hall, Kyleneen
dc.contributor.departmentBiomedical Sciences and Pathobiologyen
dc.date.accessioned2021-03-15T11:41:47Zen
dc.date.available2021-03-15T11:41:47Zen
dc.date.issued2021-03-02en
dc.date.updated2021-03-12T14:39:40Zen
dc.description.abstractAlphaviruses are a genus of the <i>Togaviridae</i> family and are widely distributed across the globe. Venezuelan equine encephalitis virus (VEEV) and eastern equine encephalitis virus (EEEV), cause encephalitis and neurological sequelae while chikungunya virus (CHIKV) and Sindbis virus (SINV) cause arthralgia. There are currently no approved therapeutics or vaccines available for alphaviruses. In order to identify novel therapeutics, a V5 epitope tag was inserted into the N-terminus of the VEEV E2 glycoprotein and used to identify host-viral protein interactions. Host proteins involved in protein folding, metabolism/ATP production, translation, cytoskeleton, complement, vesicle transport and ubiquitination were identified as VEEV E2 interactors. Multiple inhibitors targeting these host proteins were tested to determine their effect on VEEV replication. The compound HA15, a GRP78 inhibitor, was found to be an effective inhibitor of VEEV, EEEV, CHIKV, and SINV. VEEV E2 interaction with GRP78 was confirmed through coimmunoprecipitation and colocalization experiments. Mechanism of action studies found that HA15 does not affect viral RNA replication but instead affects late stages of the viral life cycle, which is consistent with GRP78 promoting viral assembly or viral protein trafficking.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationBarrera, M.D.; Callahan, V.; Akhrymuk, I.; Bhalla, N.; Zhou, W.; Campbell, C.; Narayanan, A.; Kehn-Hall, K. Proteomic Discovery of VEEV E2-Host Partner Interactions Identifies GRP78 Inhibitor HA15 as a Potential Therapeutic for Alphavirus Infections. Pathogens 2021, 10, 283.en
dc.identifier.doihttps://doi.org/10.3390/pathogens10030283en
dc.identifier.urihttp://hdl.handle.net/10919/102712en
dc.language.isoenen
dc.publisherMDPIen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectE2en
dc.subjectglycoproteinen
dc.subjectGRP78en
dc.subjectalphavirusen
dc.subjecttherapeuticen
dc.subjectproteomicsen
dc.titleProteomic Discovery of VEEV E2-Host Partner Interactions Identifies GRP78 Inhibitor HA15 as a Potential Therapeutic for Alphavirus Infectionsen
dc.title.serialPathogensen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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Journal Articles, Multidisciplinary Digital Publishing Institute (MDPI)
Destination Area: Global Systems Science (GSS)
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