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Transthyretin chemical chaperoning by flavonoids: Structure–activity insights towards the design of potent amyloidosis inhibitors

BACKGROUND: Many polyphenols have been proposed as broad-spectrum inhibitors of amyloid formation. To investigate structure–activity relationships relevant for the interaction of flavonoids with transthyretin (TTR), the protein associated with familial amyloid polyneuropathy (FAP), we compared the e...

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Autores principales: Ferreira, Nelson, Pereira-Henriques, Alda, Almeida, Maria Rosário
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668852/
https://www.ncbi.nlm.nih.gov/pubmed/29124175
http://dx.doi.org/10.1016/j.bbrep.2015.07.019
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author Ferreira, Nelson
Pereira-Henriques, Alda
Almeida, Maria Rosário
author_facet Ferreira, Nelson
Pereira-Henriques, Alda
Almeida, Maria Rosário
author_sort Ferreira, Nelson
collection PubMed
description BACKGROUND: Many polyphenols have been proposed as broad-spectrum inhibitors of amyloid formation. To investigate structure–activity relationships relevant for the interaction of flavonoids with transthyretin (TTR), the protein associated with familial amyloid polyneuropathy (FAP), we compared the effects of major tea catechins and their larger polymers theaflavins, side-by-side, on TTR amyloid formation process. METHODS: Interaction of flavonoids with TTR and effect on TTR stability were assessed through binding assays and isoelectric focusing in polyacrylamide gel. TTR aggregation was studied, in vitro, by dynamic light scattering (DLS), transmission electron microscopy (TEM) and in cell culture, through cytotoxicity assays. RESULTS: Tested flavonoids bound to TTR and stabilized the TTR tetramer, with different potencies. The flavonoids also inhibited in vitro formation of TTR small oligomeric species and in cell culture inhibited pathways involving caspase-3 activation and ER stress that are induced by TTR oligomers. In all assays performed the galloyl esters presented higher potency to inhibit aggregation than the non-gallated flavonoids tested. CONCLUSIONS: Our results highlight the presence of gallate ester moiety as key structural feature of flavonoids in chemical chaperoning of TTR aggregation. Upon binding to the native tetramer, gallated flavonoids redirect the TTR amyloidogenic pathway into unstructured nontoxic aggregation assemblies more efficiently than their non-gallated forms. GENERAL SIGNIFICANCE: Our findings suggest that galloyl moieties greatly enhance flavonoid anti-amyloid chaperone activity and this should be taken into consideration in therapeutic candidate drug discovery.
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spelling pubmed-56688522017-11-09 Transthyretin chemical chaperoning by flavonoids: Structure–activity insights towards the design of potent amyloidosis inhibitors Ferreira, Nelson Pereira-Henriques, Alda Almeida, Maria Rosário Biochem Biophys Rep Research Article BACKGROUND: Many polyphenols have been proposed as broad-spectrum inhibitors of amyloid formation. To investigate structure–activity relationships relevant for the interaction of flavonoids with transthyretin (TTR), the protein associated with familial amyloid polyneuropathy (FAP), we compared the effects of major tea catechins and their larger polymers theaflavins, side-by-side, on TTR amyloid formation process. METHODS: Interaction of flavonoids with TTR and effect on TTR stability were assessed through binding assays and isoelectric focusing in polyacrylamide gel. TTR aggregation was studied, in vitro, by dynamic light scattering (DLS), transmission electron microscopy (TEM) and in cell culture, through cytotoxicity assays. RESULTS: Tested flavonoids bound to TTR and stabilized the TTR tetramer, with different potencies. The flavonoids also inhibited in vitro formation of TTR small oligomeric species and in cell culture inhibited pathways involving caspase-3 activation and ER stress that are induced by TTR oligomers. In all assays performed the galloyl esters presented higher potency to inhibit aggregation than the non-gallated flavonoids tested. CONCLUSIONS: Our results highlight the presence of gallate ester moiety as key structural feature of flavonoids in chemical chaperoning of TTR aggregation. Upon binding to the native tetramer, gallated flavonoids redirect the TTR amyloidogenic pathway into unstructured nontoxic aggregation assemblies more efficiently than their non-gallated forms. GENERAL SIGNIFICANCE: Our findings suggest that galloyl moieties greatly enhance flavonoid anti-amyloid chaperone activity and this should be taken into consideration in therapeutic candidate drug discovery. Elsevier 2015-08-01 /pmc/articles/PMC5668852/ /pubmed/29124175 http://dx.doi.org/10.1016/j.bbrep.2015.07.019 Text en © 2015 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Ferreira, Nelson
Pereira-Henriques, Alda
Almeida, Maria Rosário
Transthyretin chemical chaperoning by flavonoids: Structure–activity insights towards the design of potent amyloidosis inhibitors
title Transthyretin chemical chaperoning by flavonoids: Structure–activity insights towards the design of potent amyloidosis inhibitors
title_full Transthyretin chemical chaperoning by flavonoids: Structure–activity insights towards the design of potent amyloidosis inhibitors
title_fullStr Transthyretin chemical chaperoning by flavonoids: Structure–activity insights towards the design of potent amyloidosis inhibitors
title_full_unstemmed Transthyretin chemical chaperoning by flavonoids: Structure–activity insights towards the design of potent amyloidosis inhibitors
title_short Transthyretin chemical chaperoning by flavonoids: Structure–activity insights towards the design of potent amyloidosis inhibitors
title_sort transthyretin chemical chaperoning by flavonoids: structure–activity insights towards the design of potent amyloidosis inhibitors
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668852/
https://www.ncbi.nlm.nih.gov/pubmed/29124175
http://dx.doi.org/10.1016/j.bbrep.2015.07.019
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