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theLiTEā„¢: a screening platform to identify compounds that reinforce tight junctions

2022-01Journal article Open access
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dc.contributor.authorGomes, Teresa Lopes
dc.contributor.authorOliveira-Marques, VirgĆ­nia de
dc.contributor.authorHampson, Richard John
dc.contributor.authorJacinto, AntĆ³nio
dc.contributor.authorde Moraes, Luciana Vieira
dc.contributor.authorMartinho, Rui Goncalo
dc.date.accessioned2022-02-16T15:28:38Z
dc.date.available2022-02-16T15:28:38Z
dc.date.issued2022-01
dc.description.abstractTight junctions (TJ) are formed by transmembrane and intracellular proteins that seal the intercellular space and control selective permeability of epithelia. Integrity of the epithelial barrier is central to tissue homeostasis and barrier dysfunction has been linked to many pathological conditions. TJ support the maintenance of cell polarity through interactions with the Par complex (Cdc42-Par-6-Par-3-aPKC) in which Par-6 is an adaptor and links the proteins of the complex together. Studies have shown that Par-6 overexpression delays the assembly of TJ proteins suggesting that Par-6 negatively regulates TJ assembly. Because restoring barrier integrity is of key therapeutic and prophylactic value, we focus on finding compounds that have epithelial barrier reinforcement properties; we developed a screening platform (theLiTEā„¢) to identify compounds that modulate Par-6 expression in follicular epithelial cells from Par-6-GFP Drosophila melanogaster egg chambers. Hits identified were then tested whether they improve epithelial barrier function, using measurements of transepithelial electrical resistance (TEER) or dye efflux to evaluate paracellular permeability. We tested 2,400 compounds, found in total 10 hits. Here we present data on six of them: the first four hits allowed us to sequentially build confidence in theLiTEā„¢ and two compounds that were shortlisted for further development (myricetin and quercetin). We selected quercetin due to its clinical and scientific validation as a compound that regulates TJ; food supplement formulated on the basis of this discovery is currently undergoing clinical evaluation in gastroesophageal reflux disease (GERD) sufferers.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.3389/fphar.2021.752787pt_PT
dc.identifier.issn1663-9812
dc.identifier.urihttp://hdl.handle.net/10400.1/17563
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherFrontiers Media SApt_PT
dc.relationA novel drug candidate for the treatment of Eosinophilic Esophagitis - an innovative solution for a significant unmet medical need
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectPAR-6pt_PT
dc.subjectEpithelial cellspt_PT
dc.subjectTight junctionspt_PT
dc.subjectQuercetinpt_PT
dc.subjectMyricetinpt_PT
dc.subjectPolarity (cell)pt_PT
dc.titletheLiTEā„¢: a screening platform to identify compounds that reinforce tight junctionspt_PT
dc.title.alternativetheLiTE (TM): uma plataforma de triagem para identificar compostos que reforƧam junƧƵes apertadaspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleA novel drug candidate for the treatment of Eosinophilic Esophagitis - an innovative solution for a significant unmet medical need
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/745175/EU
oaire.citation.titleFrontiers in Pharmacologypt_PT
oaire.citation.volume12pt_PT
oaire.fundingStreamH2020
person.familyNameViegas Russo da ConceiĆ§Ć£o Martinho
person.givenNameRui GonƧalo
person.identifier.ciencia-idF31D-C783-3D89
person.identifier.orcid0000-0002-1641-3403
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameEuropean Commission
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication8891c3b2-0f45-4db4-8772-b1dadcf89585
relation.isAuthorOfPublication.latestForDiscovery8891c3b2-0f45-4db4-8772-b1dadcf89585
relation.isProjectOfPublication48cc1b39-3186-4282-973a-405dd7b38790
relation.isProjectOfPublication.latestForDiscovery48cc1b39-3186-4282-973a-405dd7b38790

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