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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

Determining the selectivity of TBBPA and tafamidis for TTR in human plasma.TBBPA and tafamidis were titrated at different concentrations in human plasma from a single healthy donor and incubated for 2 h. The dissociation of plasma TTR was initiated by the addition of urea at a final concentration of 4.0 M. The dissociation to monomeric TTR was monitored by western blot and quantified with the ImageJ 2.0 software. The inhibitory concentration at 50% in plasma (IC50) was estimated from three independent experiments. (A) TBBPA. (B) Tafamidis.
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pone.0153529.g003: Determining the selectivity of TBBPA and tafamidis for TTR in human plasma.TBBPA and tafamidis were titrated at different concentrations in human plasma from a single healthy donor and incubated for 2 h. The dissociation of plasma TTR was initiated by the addition of urea at a final concentration of 4.0 M. The dissociation to monomeric TTR was monitored by western blot and quantified with the ImageJ 2.0 software. The inhibitory concentration at 50% in plasma (IC50) was estimated from three independent experiments. (A) TBBPA. (B) Tafamidis.

Mentions: The ability of a drug to stabilize the tetrameric form of TTR by binding to the hydrophobic hormone binding pockets at the dimer interface of the tetramer is directly correlated to the drug’s binding affinity. However, the effective concentration of the drug can be compromised by nonspecific binding to other components that are present in plasma, and this can result in poor selectivity. We have recently developed an assay that determines the ability of a drug to stabilize TTR in the presence of human plasma. The tetrameric concentration of TTR in vivo is approximately 5 μM (0.28 mg/ml), and this sets the lower concentration limit for the drug. Using this assay, we found that TBBPA is highly specific and effectively stabilizes TTR at a stoichiometric ratio in plasma (Fig 3A). The highly selective drug tafamidis was included for comparison and is shown in Fig 3B.


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)

Determining the selectivity of TBBPA and tafamidis for TTR in human plasma.TBBPA and tafamidis were titrated at different concentrations in human plasma from a single healthy donor and incubated for 2 h. The dissociation of plasma TTR was initiated by the addition of urea at a final concentration of 4.0 M. The dissociation to monomeric TTR was monitored by western blot and quantified with the ImageJ 2.0 software. The inhibitory concentration at 50% in plasma (IC50) was estimated from three independent experiments. (A) TBBPA. (B) Tafamidis.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0153529.g003: Determining the selectivity of TBBPA and tafamidis for TTR in human plasma.TBBPA and tafamidis were titrated at different concentrations in human plasma from a single healthy donor and incubated for 2 h. The dissociation of plasma TTR was initiated by the addition of urea at a final concentration of 4.0 M. The dissociation to monomeric TTR was monitored by western blot and quantified with the ImageJ 2.0 software. The inhibitory concentration at 50% in plasma (IC50) was estimated from three independent experiments. (A) TBBPA. (B) Tafamidis.
Mentions: The ability of a drug to stabilize the tetrameric form of TTR by binding to the hydrophobic hormone binding pockets at the dimer interface of the tetramer is directly correlated to the drug’s binding affinity. However, the effective concentration of the drug can be compromised by nonspecific binding to other components that are present in plasma, and this can result in poor selectivity. We have recently developed an assay that determines the ability of a drug to stabilize TTR in the presence of human plasma. The tetrameric concentration of TTR in vivo is approximately 5 μM (0.28 mg/ml), and this sets the lower concentration limit for the drug. Using this assay, we found that TBBPA is highly specific and effectively stabilizes TTR at a stoichiometric ratio in plasma (Fig 3A). The highly selective drug tafamidis was included for comparison and is shown in Fig 3B.

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