Binding of epigallocatechin‐3‐gallate to transthyretin modulates its amyloidogenicity

Ferreira, Nelson; Cardoso, Isabel; Domingues, Rosário M.; Vitorino, Rui; Bastos, Margarida; Bai, Guangyue; Saraiva, Maria João; Almeida, Maria Rosário

doi:10.1016/j.febslet.2009.10.062

Cited by 127 publications

(129 citation statements)

References 29 publications

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“…The results demonstrated that these phytochemicals disrupted pre-formed amyloid fibrils, though with different potency. EGCG powerfully disrupted mature TTR fibrils into a very polydisperse population of protein aggregates supporting results obtained for other amyloidogenic variants [13]. Curcumin markedly disaggregated amyloid fibrils, originating a particular population of small amorphous aggregates, morphologically similar to previously reported curcumin destabilized Ab fibrils [15].…”

Section: Discussionsupporting

confidence: 84%

“…Aliquots from the samples studied by DLS were also analyzed by TEM as previously reported [13,16]. Sample aliquots (5 ll) were adsorbed to carbon-coated collodion film supported on 200-mesh copper grids.…”

Section: Dynamic Light Scattering (Dls) and Transmission Electron Micmentioning

confidence: 99%

“…However some of the previously suggested compounds present low binding affinity or low selectivity of binding to TTR ex vivo and, in some cases, severe adverse side effects associated with their administration in vivo [10][11][12]. Recently, our group reported that (À)-epigallocatechin gallate (EGCG), the most abundant catechin in green tea, inhibits TTR aggregation in vitro [13] raising the possibility of using this polyphenol or analogs to treat FAP.…”

Section: Introductionmentioning

confidence: 99%

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Natural polyphenols inhibit different steps of the process of transthyretin (TTR) amyloid fibril formation

Ferreira¹,

Saraiva

Almeida³

2011

FEBS Letters

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139

126

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Edited by Jesus AvilaKeywords: Transthyretin Amyloid inhibitor Fibril formation (À)-Epigallocatechin-3-gallate Curcumin a b s t r a c t Several natural polyphenols with potent inhibitory effects on amyloid fibril formation have been reported. Herein, we studied modulation of transthyretin (TTR) fibrillogenesis by selected polyphenols. We demonstrate that both curcumin and nordihydroguaiaretic acid (NDGA) bind to TTR and stabilize the TTR tetramer. However, while NDGA slightly reduced TTR aggregation, curcumin strongly suppressed TTR amyloid fibril formation by generating small ''off-pathway'' oligomers and EGCG maintained most of the protein in a non-aggregated soluble form. This indicates alternative mechanisms of action supported by the occurrence of different non-toxic intermediates. Moreover, EGCG and curcumin efficiently disaggregated pre-formed TTR amyloid fibrils. Our studies, together with the safe toxicological profile of these phytochemicals may guide a novel pharmacotherapy for TTR-related amyloidosis targeting different steps in fibrillogenesis. Structured summary of protein interactions:TTR binds to TTR by comigration in gel electrophoresis (View interaction) TTR binds to TTR by dynamic light scattering (View interaction) TTR binds to TTR by electron microscopy (View interaction)

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Section: Discussionsupporting

confidence: 84%

Section: Dynamic Light Scattering (Dls) and Transmission Electron Micmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Natural polyphenols inhibit different steps of the process of transthyretin (TTR) amyloid fibril formation

Ferreira¹,

Saraiva

Almeida³

2011

FEBS Letters

Self Cite

139

126

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“…assessed by binding assays using control plasma 6, TTR alone was mainly fibrillar whereas the EGCG-containing preparations did not change [155]. Similarly, EGCG was found to inhibit TTR aggregation in media of a rat Schwannoma cell line, which secretes TTR Leu55→Pro, as determined by a filter-binding assay [155].…”

Section: Egcg: Egcg Interaction With Ttr Wasmentioning

confidence: 99%

Modulators of amyloid protein aggregation and toxicity: EGCG and CLR01

Attar

Rahimi

Bitan

2013

Translational Neuroscience

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Abnormal protein folding and self-assembly causes over 30 cureless human diseases for which no diseasemodifying therapies are available. The common side to all these diseases is formation of aberrant toxic protein oligomers and amyloid fibrils. Both types of assemblies are drug targets, yet each presents major challenges to drug design, discovery, and development. In this review, we focus on two small molecules that inhibit formation of toxic amyloid protein assemblies -the green-tea derivative (-)-epigallocatechin-3-gallate (EGCG), which was identified through a combination of epidemiologic data and a compound library screen, and the molecular tweezer CLR01, whose inhibitory activity was discovered in our group based on rational reasoning, and subsequently confirmed experimentally. Both compounds act in a manner that is not specific to one particular protein and thus are useful against a multitude of amyloidogenic proteins, yet they act via distinct putative mechanisms. CLR01 disrupts protein aggregation through specific binding to lysine residues, whereas the mechanisms underlying the activity of EGCG are only recently beginning to unveil. We discuss current in vitro and, where available, in vivo literature related to EGCG and CLR01's effects on amyloid β-protein, α-synuclein, transthyretin, islet amyloid polypeptide, and calcitonin. We also describe the toxicity, pharmacokinetics, and mechanism of action of each compound.

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“…Since then, it has been shown that EGCG binds directly to a large number of proteins that are involved in protein misfolding diseases and that EGCG inhibits their fibrillization. Examples include αS [81,82], Aβ [36,82], transthyretin [83], lysozyme [84], the prion protein PrP [85], and the yeast prion Sup35 [86].…”

Section: Mechanism Of Egcg Interventionmentioning

confidence: 99%

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

Bieschke

2013

Neurotherapeutics

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Protein misfolding disorders, such as Alzheimer's disease and Parkinson's disease, have in common that a protein accumulates in an insoluble form in the affected tissue. The process of aggregation follows a mechanism of seeded polymerization. Although the toxic species is still not well defined, the process, rather than the end product, of fibril formation is likely the main culprit in amyloid toxicity. These findings suggest that therapeutic strategies directed against the protein misfolding cascade should focus on depleting aggregation intermediates rather than on large fibrillar aggregates. Recent studies involving natural compounds have suggested new intervention strategies. The polyphenol epi-gallocatechine-3-gallate (EGCG), the main polyphenol in Camilla sinensis, binds directly to a large number of proteins that are involved in protein misfolding diseases and inhibits their fibrillization. Instead, it promotes the formation of stable, spherical aggregates. These spherical aggregates are not cytotoxic, have a lower β-sheet content than fibrils, and do not catalyze fibril formation. Correspondingly, epi-gallocatechine-3-gallate remodels amyloid fibrils into aggregates with the same properties. Derivatives of Orcein, which is a phenoxazine dye that can be isolated from the lichen Roccella tinctoria, form a second promising class of natural compounds. They accelerate fibril formation of the Alzheimer's disease-related amyloid-beta peptide. At the same time these compounds deplete oligomeric and protofibrillar forms of the peptide. These compounds may serve as proof-of-principle for the strategies of promoting and redirecting fibril formation. Both may emerge as two promising new therapeutic approaches to intervening into protein misfolding processes.

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Binding of epigallocatechin‐3‐gallate to transthyretin modulates its amyloidogenicity

Cited by 127 publications

References 29 publications

Natural polyphenols inhibit different steps of the process of transthyretin (TTR) amyloid fibril formation

Natural polyphenols inhibit different steps of the process of transthyretin (TTR) amyloid fibril formation

Modulators of amyloid protein aggregation and toxicity: EGCG and CLR01

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

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