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Iodine atoms: a new molecular feature for the design of potent transthyretin fibrillogenesis inhibitors.

Mairal T, Nieto J, Pinto M, Almeida MR, Gales L, Ballesteros A, Barluenga J, Pérez JJ, Vázquez JT, Centeno NB, Saraiva MJ, Damas AM, Planas A, Arsequell G, Valencia G - PLoS ONE (2009)

Bottom Line: TTR self assembles as a homotetramer leaving a central hydrophobic channel with two symmetrical binding sites.Up to now, TTR aggregation inhibitors have been designed looking at various structural features of this binding channel others than its ability to host iodine atoms.In the present work, greatly improved inhibitors have been designed and tested by taking into account that thyroid hormones are unique in human biochemistry owing to the presence of multiple iodine atoms in their molecules which are probed to interact with specific halogen binding domains sitting at the TTR binding channel.

View Article: PubMed Central - PubMed

Affiliation: Unit of Glycoconjugate Chemistry, Institut de Química Avançada de Catalunya, I.Q.A.C.-C.S.I.C., Barcelona, Spain.

ABSTRACT
The thyroid hormone and retinol transporter protein known as transthyretin (TTR) is in the origin of one of the 20 or so known amyloid diseases. TTR self assembles as a homotetramer leaving a central hydrophobic channel with two symmetrical binding sites. The aggregation pathway of TTR into amiloid fibrils is not yet well characterized but in vitro binding of thyroid hormones and other small organic molecules to TTR binding channel results in tetramer stabilization which prevents amyloid formation in an extent which is proportional to the binding constant. Up to now, TTR aggregation inhibitors have been designed looking at various structural features of this binding channel others than its ability to host iodine atoms. In the present work, greatly improved inhibitors have been designed and tested by taking into account that thyroid hormones are unique in human biochemistry owing to the presence of multiple iodine atoms in their molecules which are probed to interact with specific halogen binding domains sitting at the TTR binding channel. The new TTR fibrillogenesis inhibitors are based on the diflunisal core structure because diflunisal is a registered salicylate drug with NSAID activity now undergoing clinical trials for TTR amyloid diseases. Biochemical and biophysical evidence confirms that iodine atoms can be an important design feature in the search for candidate drugs for TTR related amyloidosis.

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Related in: MedlinePlus

Synthesis of diflunisal and iododiflunisal analogs.A) Modifying functional groups of diflunisal; B) Conjugation to α-amino acids; and C) Conjugation to β-alanine derivatives.
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pone-0004124-g004: Synthesis of diflunisal and iododiflunisal analogs.A) Modifying functional groups of diflunisal; B) Conjugation to α-amino acids; and C) Conjugation to β-alanine derivatives.

Mentions: To further examine how general was this effect on diflunisal analogues, a library of 40 derivatives has been designed and prepared. Two subsets of twin compounds have been synthesized (Figure 4). The products labeled as “a” lack iodine atoms while the ones termed as “b” show one iodine atom at C-5 position. In turn, both series include two groups of compounds, one prepared by modifiying the functional groups of diflunisal by common organic chemistry reactions (compounds 1a to 7b) and a second group originated by conjugation of diflunisal to a series of amino acids by standard peptide synthesis protocols (compounds 8a to 23b) (Figure 4 and Figure 5).


Iodine atoms: a new molecular feature for the design of potent transthyretin fibrillogenesis inhibitors.

Mairal T, Nieto J, Pinto M, Almeida MR, Gales L, Ballesteros A, Barluenga J, Pérez JJ, Vázquez JT, Centeno NB, Saraiva MJ, Damas AM, Planas A, Arsequell G, Valencia G - PLoS ONE (2009)

Synthesis of diflunisal and iododiflunisal analogs.A) Modifying functional groups of diflunisal; B) Conjugation to α-amino acids; and C) Conjugation to β-alanine derivatives.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2607018&req=5

pone-0004124-g004: Synthesis of diflunisal and iododiflunisal analogs.A) Modifying functional groups of diflunisal; B) Conjugation to α-amino acids; and C) Conjugation to β-alanine derivatives.
Mentions: To further examine how general was this effect on diflunisal analogues, a library of 40 derivatives has been designed and prepared. Two subsets of twin compounds have been synthesized (Figure 4). The products labeled as “a” lack iodine atoms while the ones termed as “b” show one iodine atom at C-5 position. In turn, both series include two groups of compounds, one prepared by modifiying the functional groups of diflunisal by common organic chemistry reactions (compounds 1a to 7b) and a second group originated by conjugation of diflunisal to a series of amino acids by standard peptide synthesis protocols (compounds 8a to 23b) (Figure 4 and Figure 5).

Bottom Line: TTR self assembles as a homotetramer leaving a central hydrophobic channel with two symmetrical binding sites.Up to now, TTR aggregation inhibitors have been designed looking at various structural features of this binding channel others than its ability to host iodine atoms.In the present work, greatly improved inhibitors have been designed and tested by taking into account that thyroid hormones are unique in human biochemistry owing to the presence of multiple iodine atoms in their molecules which are probed to interact with specific halogen binding domains sitting at the TTR binding channel.

View Article: PubMed Central - PubMed

Affiliation: Unit of Glycoconjugate Chemistry, Institut de Química Avançada de Catalunya, I.Q.A.C.-C.S.I.C., Barcelona, Spain.

ABSTRACT
The thyroid hormone and retinol transporter protein known as transthyretin (TTR) is in the origin of one of the 20 or so known amyloid diseases. TTR self assembles as a homotetramer leaving a central hydrophobic channel with two symmetrical binding sites. The aggregation pathway of TTR into amiloid fibrils is not yet well characterized but in vitro binding of thyroid hormones and other small organic molecules to TTR binding channel results in tetramer stabilization which prevents amyloid formation in an extent which is proportional to the binding constant. Up to now, TTR aggregation inhibitors have been designed looking at various structural features of this binding channel others than its ability to host iodine atoms. In the present work, greatly improved inhibitors have been designed and tested by taking into account that thyroid hormones are unique in human biochemistry owing to the presence of multiple iodine atoms in their molecules which are probed to interact with specific halogen binding domains sitting at the TTR binding channel. The new TTR fibrillogenesis inhibitors are based on the diflunisal core structure because diflunisal is a registered salicylate drug with NSAID activity now undergoing clinical trials for TTR amyloid diseases. Biochemical and biophysical evidence confirms that iodine atoms can be an important design feature in the search for candidate drugs for TTR related amyloidosis.

Show MeSH
Related in: MedlinePlus