Limits...
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

TBBPA prevents tetramer dissociation under acidic conditions.WT-TTR (A) and V30M-TTR (B) dissolved in PBS at a tetrameric concentration of 15 μM were pre-incubated alone or in the presence of TBBPA, diflunisal, or tafamidis (each at 15 μM) for 2 h. Aggregation of WT-TTR and V30M-TTR was initiated by lowering the pH to 4.5 using a sodium-acetate/acetic acid buffer followed by incubation for 72 h. The percentage of aggregation relative to the control was monitored by measuring the turbidity at 400 nm. Statistical analysis was performed using one-way ANOVA, and data are presented as the mean ± standard deviation of the percent fibril formation (n = 2, *** p < 0.001).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4836675&req=5

pone.0153529.g001: TBBPA prevents tetramer dissociation under acidic conditions.WT-TTR (A) and V30M-TTR (B) dissolved in PBS at a tetrameric concentration of 15 μM were pre-incubated alone or in the presence of TBBPA, diflunisal, or tafamidis (each at 15 μM) for 2 h. Aggregation of WT-TTR and V30M-TTR was initiated by lowering the pH to 4.5 using a sodium-acetate/acetic acid buffer followed by incubation for 72 h. The percentage of aggregation relative to the control was monitored by measuring the turbidity at 400 nm. Statistical analysis was performed using one-way ANOVA, and data are presented as the mean ± standard deviation of the percent fibril formation (n = 2, *** p < 0.001).

Mentions: Amyloid formation by TTR can be induced at low pH, which results in disruption of the tetramer and the subsequent formation of aggregates. This event can be monitored by a simple turbidity measurement. Diflunisal and tafamidis have both been previously studied for their ability to stabilize TTR tetramers [11,44], and they are included in this study only for comparison purposes. Turbidity measurements showed that TBBPA efficiently prevents the aggregation of TTR as well as the clinically relevant TTRVal30Met variant at low pH in a similar manner to diflunisal and tafamidis (Fig 1).


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)

TBBPA prevents tetramer dissociation under acidic conditions.WT-TTR (A) and V30M-TTR (B) dissolved in PBS at a tetrameric concentration of 15 μM were pre-incubated alone or in the presence of TBBPA, diflunisal, or tafamidis (each at 15 μM) for 2 h. Aggregation of WT-TTR and V30M-TTR was initiated by lowering the pH to 4.5 using a sodium-acetate/acetic acid buffer followed by incubation for 72 h. The percentage of aggregation relative to the control was monitored by measuring the turbidity at 400 nm. Statistical analysis was performed using one-way ANOVA, and data are presented as the mean ± standard deviation of the percent fibril formation (n = 2, *** p < 0.001).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0153529.g001: TBBPA prevents tetramer dissociation under acidic conditions.WT-TTR (A) and V30M-TTR (B) dissolved in PBS at a tetrameric concentration of 15 μM were pre-incubated alone or in the presence of TBBPA, diflunisal, or tafamidis (each at 15 μM) for 2 h. Aggregation of WT-TTR and V30M-TTR was initiated by lowering the pH to 4.5 using a sodium-acetate/acetic acid buffer followed by incubation for 72 h. The percentage of aggregation relative to the control was monitored by measuring the turbidity at 400 nm. Statistical analysis was performed using one-way ANOVA, and data are presented as the mean ± standard deviation of the percent fibril formation (n = 2, *** p < 0.001).
Mentions: Amyloid formation by TTR can be induced at low pH, which results in disruption of the tetramer and the subsequent formation of aggregates. This event can be monitored by a simple turbidity measurement. Diflunisal and tafamidis have both been previously studied for their ability to stabilize TTR tetramers [11,44], and they are included in this study only for comparison purposes. Turbidity measurements showed that TBBPA efficiently prevents the aggregation of TTR as well as the clinically relevant TTRVal30Met variant at low pH in a similar manner to diflunisal and tafamidis (Fig 1).

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