Anti-prion activity of a panel of aromatic chemical compounds: in vitro and in silico approaches.

The prion protein (PrP) is implicated in the Transmissible Spongiform Encephalopathies (TSEs), which comprise a group of fatal neurodegenerative diseases affecting humans and other mammals. Conversion of cellular PrP (PrP(C)) into the scrapie form (PrP(Sc)) is the hallmark of TSEs. Once formed, PrP(...

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Autores principales: Natalia C Ferreira, Icaro A Marques, Wesley A Conceição, Bruno Macedo, Clarice S Machado, Alessandra Mascarello, Louise Domeneghini Chiaradia-Delatorre, Rosendo Augusto Yunes, Ricardo José Nunes, Andrew G Hughson, Lynne D Raymond, Pedro G Pascutti, Byron Caughey, Yraima Cordeiro
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Publicado: Public Library of Science (PLoS) 2014
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spelling oai:doaj.org-article:43799d36574b4265a3fe221bb978ffb92021-11-18T08:38:51ZAnti-prion activity of a panel of aromatic chemical compounds: in vitro and in silico approaches.1932-620310.1371/journal.pone.0084531https://doaj.org/article/43799d36574b4265a3fe221bb978ffb92014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24400098/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The prion protein (PrP) is implicated in the Transmissible Spongiform Encephalopathies (TSEs), which comprise a group of fatal neurodegenerative diseases affecting humans and other mammals. Conversion of cellular PrP (PrP(C)) into the scrapie form (PrP(Sc)) is the hallmark of TSEs. Once formed, PrP(Sc) aggregates and catalyzes PrP(C) misfolding into new PrP(Sc) molecules. Although many compounds have been shown to inhibit the conversion process, so far there is no effective therapy for TSEs. Besides, most of the previously evaluated compounds failed in vivo due to poor pharmacokinetic profiles. In this work we propose a combined in vitro/in silico approach to screen for active anti-prion compounds presenting acceptable drugability and pharmacokinetic parameters. A diverse panel of aromatic compounds was screened in neuroblastoma cells persistently infected with PrP(Sc) (ScN2a) for their ability to inhibit PK-resistant PrP (PrP(Res)) accumulation. From ∼200 compounds, 47 were effective in decreasing the accumulation of PrP(Res) in ScN2a cells. Pharmacokinetic and physicochemical properties were predicted in silico, allowing us to obtain estimates of relative blood brain barrier permeation and mutagenicity. MTT reduction assays showed that most of the active compounds were non cytotoxic. Compounds that cleared PrP(Res) from ScN2a cells, were non-toxic in the MTT assay, and presented a good pharmacokinetic profile were investigated for their ability to inhibit aggregation of an amyloidogenic PrP peptide fragment (PrP(109-149)). Molecular docking results provided structural models and binding affinities for the interaction between PrP and the most promising compounds. In summary, using this combined in vitro/in silico approach we have identified new small organic anti-scrapie compounds that decrease the accumulation of PrP(Res) in ScN2a cells, inhibit the aggregation of a PrP peptide, and possess pharmacokinetic characteristics that support their drugability. These compounds are attractive candidates for prion disease therapy.Natalia C FerreiraIcaro A MarquesWesley A ConceiçãoBruno MacedoClarice S MachadoAlessandra MascarelloLouise Domeneghini Chiaradia-DelatorreRosendo Augusto YunesRicardo José NunesAndrew G HughsonLynne D RaymondPedro G PascuttiByron CaugheyYraima CordeiroPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 1, p e84531 (2014)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Natalia C Ferreira
Icaro A Marques
Wesley A Conceição
Bruno Macedo
Clarice S Machado
Alessandra Mascarello
Louise Domeneghini Chiaradia-Delatorre
Rosendo Augusto Yunes
Ricardo José Nunes
Andrew G Hughson
Lynne D Raymond
Pedro G Pascutti
Byron Caughey
Yraima Cordeiro
Anti-prion activity of a panel of aromatic chemical compounds: in vitro and in silico approaches.
description The prion protein (PrP) is implicated in the Transmissible Spongiform Encephalopathies (TSEs), which comprise a group of fatal neurodegenerative diseases affecting humans and other mammals. Conversion of cellular PrP (PrP(C)) into the scrapie form (PrP(Sc)) is the hallmark of TSEs. Once formed, PrP(Sc) aggregates and catalyzes PrP(C) misfolding into new PrP(Sc) molecules. Although many compounds have been shown to inhibit the conversion process, so far there is no effective therapy for TSEs. Besides, most of the previously evaluated compounds failed in vivo due to poor pharmacokinetic profiles. In this work we propose a combined in vitro/in silico approach to screen for active anti-prion compounds presenting acceptable drugability and pharmacokinetic parameters. A diverse panel of aromatic compounds was screened in neuroblastoma cells persistently infected with PrP(Sc) (ScN2a) for their ability to inhibit PK-resistant PrP (PrP(Res)) accumulation. From ∼200 compounds, 47 were effective in decreasing the accumulation of PrP(Res) in ScN2a cells. Pharmacokinetic and physicochemical properties were predicted in silico, allowing us to obtain estimates of relative blood brain barrier permeation and mutagenicity. MTT reduction assays showed that most of the active compounds were non cytotoxic. Compounds that cleared PrP(Res) from ScN2a cells, were non-toxic in the MTT assay, and presented a good pharmacokinetic profile were investigated for their ability to inhibit aggregation of an amyloidogenic PrP peptide fragment (PrP(109-149)). Molecular docking results provided structural models and binding affinities for the interaction between PrP and the most promising compounds. In summary, using this combined in vitro/in silico approach we have identified new small organic anti-scrapie compounds that decrease the accumulation of PrP(Res) in ScN2a cells, inhibit the aggregation of a PrP peptide, and possess pharmacokinetic characteristics that support their drugability. These compounds are attractive candidates for prion disease therapy.
format article
author Natalia C Ferreira
Icaro A Marques
Wesley A Conceição
Bruno Macedo
Clarice S Machado
Alessandra Mascarello
Louise Domeneghini Chiaradia-Delatorre
Rosendo Augusto Yunes
Ricardo José Nunes
Andrew G Hughson
Lynne D Raymond
Pedro G Pascutti
Byron Caughey
Yraima Cordeiro
author_facet Natalia C Ferreira
Icaro A Marques
Wesley A Conceição
Bruno Macedo
Clarice S Machado
Alessandra Mascarello
Louise Domeneghini Chiaradia-Delatorre
Rosendo Augusto Yunes
Ricardo José Nunes
Andrew G Hughson
Lynne D Raymond
Pedro G Pascutti
Byron Caughey
Yraima Cordeiro
author_sort Natalia C Ferreira
title Anti-prion activity of a panel of aromatic chemical compounds: in vitro and in silico approaches.
title_short Anti-prion activity of a panel of aromatic chemical compounds: in vitro and in silico approaches.
title_full Anti-prion activity of a panel of aromatic chemical compounds: in vitro and in silico approaches.
title_fullStr Anti-prion activity of a panel of aromatic chemical compounds: in vitro and in silico approaches.
title_full_unstemmed Anti-prion activity of a panel of aromatic chemical compounds: in vitro and in silico approaches.
title_sort anti-prion activity of a panel of aromatic chemical compounds: in vitro and in silico approaches.
publisher Public Library of Science (PLoS)
publishDate 2014
url https://doaj.org/article/43799d36574b4265a3fe221bb978ffb9
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