Logo do repositório
 
Publicação

Increased efficacy of VX-809 in different cellular systems results from an early stabilization effect of F508del-CFTR

2015-08-01Artigo científico Acesso aberto
Ver registo simples
dc.contributor.authorFarinha, Carlos M.
dc.contributor.authorSousa, Marisa
dc.contributor.authorCanato, Sara
dc.contributor.authorSchmidt, André
dc.contributor.authorUliyakina, Inna
dc.contributor.authorAmaral, Margarida D.
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.pblWiley-Blackwell Publishing Ltd
dc.date.accessioned2024-05-01T01:06:40Z
dc.date.available2024-05-01T01:06:40Z
dc.date.issued2015-08-01
dc.descriptionPublisher Copyright: © 2015 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.
dc.description.abstractCystic fibrosis (CF), the most common recessive autosomal disease among Caucasians, is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, F508del, leads to CFTR impaired plasma membrane trafficking. Therapies modulating CFTR basic defect are emerging, such as VX-809, a corrector of F508del-CFTR traffic which just succeeded in a Phase III clinical trial. We recently showed that VX-809 is additive to two other correctors (VRT-325 and compound 4a). Here, we aimed to determine whether the differential rescuing by these compounds results from cell-specific factors or rather from distinct effects at the early biogenesis and/or processing. The rescuing efficiencies of the above three correctors were first compared in different cellular models (primary respiratory cells, cystic fibrosis bronchial epithelial and baby hamster kidney [BHK] cell lines) by functional approaches: micro-Ussing chamber and iodide efflux. Next, biochemical methods (metabolic labeling, pulse-chase and immunoprecipitation) were used to determine their impact on CFTR biogenesis / processing. Functional analyses revealed that VX-809 has the greatest rescuing efficacy and that the relative efficiencies of the three compounds are essentially maintained in all three cellular models tested. Nevertheless, biochemical data show that VX-809 significantly stabilizes F508del-CFTR immature form, an effect that is not observed for C3 nor C4. VX-809 and C3 also significantly increase accumulation of immature CFTR. Our data suggest that VX-809 increases the stability of F508del-CFTR immature form at an early phase of its biogenesis, thus explaining its increased efficacy when inducing its rescue.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent577091
dc.identifier.doi10.1002/prp2.152
dc.identifier.issn2052-1707
dc.identifier.otherPURE: 89546394
dc.identifier.otherPURE UUID: a6587b5c-2852-493a-8472-29517fb8147b
dc.identifier.otherScopus: 84969374206
dc.identifier.urihttp://hdl.handle.net/10362/166836
dc.identifier.urlhttps://www.scopus.com/pages/publications/84969374206
dc.language.isoeng
dc.peerreviewedyes
dc.subjectCellular systems
dc.subjectCFTR function
dc.subjectCFTR modulators
dc.subjectmechanism of action
dc.subjectnovel therapies
dc.subjectNeurology
dc.subjectPharmacology, Toxicology and Pharmaceutics(all)
dc.titleIncreased efficacy of VX-809 in different cellular systems results from an early stabilization effect of F508del-CFTRen
dc.typejournal article
degois.publication.issue4
degois.publication.titlePharmacology Research and Perspectives
degois.publication.volume3
dspace.entity.typePublication
rcaap.rightsopenAccess

Ficheiros

Principais
A mostrar 1 - 1 de 1
Miniatura
Nome:
Pharmacology_Res_Perspec_-_2015_-_Farinha_-_Increased_efficacy_of_VX_809_in_different_cellular_systems_results_from_an.pdf
Tamanho:
563.57 KB
Formato:
Adobe Portable Document Format
Ver/Abrir

Coleções

NMS - Artigos em revista internacional com arbitragem científica