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Tetrabromobisphenol A Is an Efficient Stabilizer of the Transthyretin Tetramer.

Iakovleva I, Begum A, Brännström K, Wijsekera A, Nilsson L, Zhang J, Andersson PL, Sauer-Eriksson AE, Olofsson A - PLoS ONE (2016)

Bottom Line: The desired features for an effective TTR stabilizer include high affinity for TTR, high selectivity in the presence of other proteins, no adverse side effects at the effective concentrations, and a long half-life in the body.Interestingly, TBBPA binds TTR with an extremely high selectivity in human plasma, and the effect is equal to the recently approved drug tafamidis and better than diflunisal, both of which have shown therapeutic effects against FAP.Its absorption, metabolism, and potential side-effects are discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.

ABSTRACT
Amyloid formation of the human plasma protein transthyretin (TTR) is associated with several human disorders, including familial amyloidotic polyneuropathy (FAP) and senile systemic amyloidosis. Dissociation of TTR's native tetrameric assembly is the rate-limiting step in the conversion into amyloid, and this feature presents an avenue for intervention because binding of an appropriate ligand to the thyroxin hormone binding sites of TTR stabilizes the native tetrameric assembly and impairs conversion into amyloid. The desired features for an effective TTR stabilizer include high affinity for TTR, high selectivity in the presence of other proteins, no adverse side effects at the effective concentrations, and a long half-life in the body. In this study we show that the commonly used flame retardant tetrabromobisphenol A (TBBPA) efficiently stabilizes the tetrameric structure of TTR. The X-ray crystal structure shows TBBPA binding in the thyroxine binding pocket with bromines occupying two of the three halogen binding sites. Interestingly, TBBPA binds TTR with an extremely high selectivity in human plasma, and the effect is equal to the recently approved drug tafamidis and better than diflunisal, both of which have shown therapeutic effects against FAP. TBBPA consequently present an interesting scaffold for drug design. Its absorption, metabolism, and potential side-effects are discussed.

No MeSH data available.


Related in: MedlinePlus

Probing the ability of the compounds to prevent TTR-mediated cytotoxicity in a human neuronal cell line.TTR at a final tetrameric concentration of 15 μM was pre-incubated with TBBPA, diflunisal, or tafamidis (15 μM each) for 2 h. TTR or the TTR with inhibitor complexes were added to SH-SY5Y cells and incubated for 72 h. Cell viability was measured with a resazurin assay [46]. Data are reported as the mean cell viability ± the standard deviation (n = 3, ** p < 0.01; *** p < 0.001). The addition of TTR tetramer stabilizers leads to a statistically significant increase in the number of viable cells compared to cells exposed to TTR alone. The statistical significance was assessed using one-way ANOVA.
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pone.0153529.g002: Probing the ability of the compounds to prevent TTR-mediated cytotoxicity in a human neuronal cell line.TTR at a final tetrameric concentration of 15 μM was pre-incubated with TBBPA, diflunisal, or tafamidis (15 μM each) for 2 h. TTR or the TTR with inhibitor complexes were added to SH-SY5Y cells and incubated for 72 h. Cell viability was measured with a resazurin assay [46]. Data are reported as the mean cell viability ± the standard deviation (n = 3, ** p < 0.01; *** p < 0.001). The addition of TTR tetramer stabilizers leads to a statistically significant increase in the number of viable cells compared to cells exposed to TTR alone. The statistical significance was assessed using one-way ANOVA.

Mentions: It is known that preservation of tetrameric integrity also impairs the ability of TTR to exert a cytotoxic effect [45]. To evaluate the ability of TBBPA to suppress TTR-induced toxicity, we used a cell-viability assay based on human SH-SY5Y neuroblastoma cells [46]. TTR tetramers at 15 μM were incubated with cells and with or without compounds for 72 h. The cytotoxic effect of TTR was monitored by a decrease in the conversion of resazurin to resorufin. Incubation with TTR alone resulted in a 65% reduction in cell survival, and the addition of equimolar concentrations (15 μM) of TBBPA, tafamidis, or diflunisal increased cell survival to essentially that of the untreated control cells (Fig 2).


Tetrabromobisphenol A Is an Efficient Stabilizer of the Transthyretin Tetramer.

Iakovleva I, Begum A, Brännström K, Wijsekera A, Nilsson L, Zhang J, Andersson PL, Sauer-Eriksson AE, Olofsson A - PLoS ONE (2016)

Probing the ability of the compounds to prevent TTR-mediated cytotoxicity in a human neuronal cell line.TTR at a final tetrameric concentration of 15 μM was pre-incubated with TBBPA, diflunisal, or tafamidis (15 μM each) for 2 h. TTR or the TTR with inhibitor complexes were added to SH-SY5Y cells and incubated for 72 h. Cell viability was measured with a resazurin assay [46]. Data are reported as the mean cell viability ± the standard deviation (n = 3, ** p < 0.01; *** p < 0.001). The addition of TTR tetramer stabilizers leads to a statistically significant increase in the number of viable cells compared to cells exposed to TTR alone. The statistical significance was assessed using one-way ANOVA.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836675&req=5

pone.0153529.g002: Probing the ability of the compounds to prevent TTR-mediated cytotoxicity in a human neuronal cell line.TTR at a final tetrameric concentration of 15 μM was pre-incubated with TBBPA, diflunisal, or tafamidis (15 μM each) for 2 h. TTR or the TTR with inhibitor complexes were added to SH-SY5Y cells and incubated for 72 h. Cell viability was measured with a resazurin assay [46]. Data are reported as the mean cell viability ± the standard deviation (n = 3, ** p < 0.01; *** p < 0.001). The addition of TTR tetramer stabilizers leads to a statistically significant increase in the number of viable cells compared to cells exposed to TTR alone. The statistical significance was assessed using one-way ANOVA.
Mentions: It is known that preservation of tetrameric integrity also impairs the ability of TTR to exert a cytotoxic effect [45]. To evaluate the ability of TBBPA to suppress TTR-induced toxicity, we used a cell-viability assay based on human SH-SY5Y neuroblastoma cells [46]. TTR tetramers at 15 μM were incubated with cells and with or without compounds for 72 h. The cytotoxic effect of TTR was monitored by a decrease in the conversion of resazurin to resorufin. Incubation with TTR alone resulted in a 65% reduction in cell survival, and the addition of equimolar concentrations (15 μM) of TBBPA, tafamidis, or diflunisal increased cell survival to essentially that of the untreated control cells (Fig 2).

Bottom Line: The desired features for an effective TTR stabilizer include high affinity for TTR, high selectivity in the presence of other proteins, no adverse side effects at the effective concentrations, and a long half-life in the body.Interestingly, TBBPA binds TTR with an extremely high selectivity in human plasma, and the effect is equal to the recently approved drug tafamidis and better than diflunisal, both of which have shown therapeutic effects against FAP.Its absorption, metabolism, and potential side-effects are discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.

ABSTRACT
Amyloid formation of the human plasma protein transthyretin (TTR) is associated with several human disorders, including familial amyloidotic polyneuropathy (FAP) and senile systemic amyloidosis. Dissociation of TTR's native tetrameric assembly is the rate-limiting step in the conversion into amyloid, and this feature presents an avenue for intervention because binding of an appropriate ligand to the thyroxin hormone binding sites of TTR stabilizes the native tetrameric assembly and impairs conversion into amyloid. The desired features for an effective TTR stabilizer include high affinity for TTR, high selectivity in the presence of other proteins, no adverse side effects at the effective concentrations, and a long half-life in the body. In this study we show that the commonly used flame retardant tetrabromobisphenol A (TBBPA) efficiently stabilizes the tetrameric structure of TTR. The X-ray crystal structure shows TBBPA binding in the thyroxine binding pocket with bromines occupying two of the three halogen binding sites. Interestingly, TBBPA binds TTR with an extremely high selectivity in human plasma, and the effect is equal to the recently approved drug tafamidis and better than diflunisal, both of which have shown therapeutic effects against FAP. TBBPA consequently present an interesting scaffold for drug design. Its absorption, metabolism, and potential side-effects are discussed.

No MeSH data available.


Related in: MedlinePlus