Cargando…

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

Alphaviruses are a genus of the Togaviridae 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 arthra...

Descripción completa

Detalles Bibliográficos
Autores principales: Barrera, Michael D., Callahan, Victoria, Akhrymuk, Ivan, Bhalla, Nishank, Zhou, Weidong, Campbell, Catherine, Narayanan, Aarthi, Kehn-Hall, Kylene
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000471/
https://www.ncbi.nlm.nih.gov/pubmed/33801554
http://dx.doi.org/10.3390/pathogens10030283
_version_ 1783671007241830400
author Barrera, Michael D.
Callahan, Victoria
Akhrymuk, Ivan
Bhalla, Nishank
Zhou, Weidong
Campbell, Catherine
Narayanan, Aarthi
Kehn-Hall, Kylene
author_facet Barrera, Michael D.
Callahan, Victoria
Akhrymuk, Ivan
Bhalla, Nishank
Zhou, Weidong
Campbell, Catherine
Narayanan, Aarthi
Kehn-Hall, Kylene
author_sort Barrera, Michael D.
collection PubMed
description Alphaviruses are a genus of the Togaviridae 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.
format Online
Article
Text
id pubmed-8000471
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-80004712021-03-28 Proteomic Discovery of VEEV E2-Host Partner Interactions Identifies GRP78 Inhibitor HA15 as a Potential Therapeutic for Alphavirus Infections Barrera, Michael D. Callahan, Victoria Akhrymuk, Ivan Bhalla, Nishank Zhou, Weidong Campbell, Catherine Narayanan, Aarthi Kehn-Hall, Kylene Pathogens Article Alphaviruses are a genus of the Togaviridae 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. MDPI 2021-03-02 /pmc/articles/PMC8000471/ /pubmed/33801554 http://dx.doi.org/10.3390/pathogens10030283 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Barrera, Michael D.
Callahan, Victoria
Akhrymuk, Ivan
Bhalla, Nishank
Zhou, Weidong
Campbell, Catherine
Narayanan, Aarthi
Kehn-Hall, Kylene
Proteomic Discovery of VEEV E2-Host Partner Interactions Identifies GRP78 Inhibitor HA15 as a Potential Therapeutic for Alphavirus Infections
title Proteomic Discovery of VEEV E2-Host Partner Interactions Identifies GRP78 Inhibitor HA15 as a Potential Therapeutic for Alphavirus Infections
title_full Proteomic Discovery of VEEV E2-Host Partner Interactions Identifies GRP78 Inhibitor HA15 as a Potential Therapeutic for Alphavirus Infections
title_fullStr Proteomic Discovery of VEEV E2-Host Partner Interactions Identifies GRP78 Inhibitor HA15 as a Potential Therapeutic for Alphavirus Infections
title_full_unstemmed Proteomic Discovery of VEEV E2-Host Partner Interactions Identifies GRP78 Inhibitor HA15 as a Potential Therapeutic for Alphavirus Infections
title_short Proteomic Discovery of VEEV E2-Host Partner Interactions Identifies GRP78 Inhibitor HA15 as a Potential Therapeutic for Alphavirus Infections
title_sort proteomic discovery of veev e2-host partner interactions identifies grp78 inhibitor ha15 as a potential therapeutic for alphavirus infections
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000471/
https://www.ncbi.nlm.nih.gov/pubmed/33801554
http://dx.doi.org/10.3390/pathogens10030283
work_keys_str_mv AT barreramichaeld proteomicdiscoveryofveeve2hostpartnerinteractionsidentifiesgrp78inhibitorha15asapotentialtherapeuticforalphavirusinfections
AT callahanvictoria proteomicdiscoveryofveeve2hostpartnerinteractionsidentifiesgrp78inhibitorha15asapotentialtherapeuticforalphavirusinfections
AT akhrymukivan proteomicdiscoveryofveeve2hostpartnerinteractionsidentifiesgrp78inhibitorha15asapotentialtherapeuticforalphavirusinfections
AT bhallanishank proteomicdiscoveryofveeve2hostpartnerinteractionsidentifiesgrp78inhibitorha15asapotentialtherapeuticforalphavirusinfections
AT zhouweidong proteomicdiscoveryofveeve2hostpartnerinteractionsidentifiesgrp78inhibitorha15asapotentialtherapeuticforalphavirusinfections
AT campbellcatherine proteomicdiscoveryofveeve2hostpartnerinteractionsidentifiesgrp78inhibitorha15asapotentialtherapeuticforalphavirusinfections
AT narayananaarthi proteomicdiscoveryofveeve2hostpartnerinteractionsidentifiesgrp78inhibitorha15asapotentialtherapeuticforalphavirusinfections
AT kehnhallkylene proteomicdiscoveryofveeve2hostpartnerinteractionsidentifiesgrp78inhibitorha15asapotentialtherapeuticforalphavirusinfections