Structural stabilization of transthyretin by a new compound, 6-benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione

Takeshi Yokoyama; Shun Takaki; Keisuke Chosa; Takashi Sato; Mary Ann Suico; Yuriko Teranishi; Tsuyoshi Shuto; Mineyuki Mizuguchi; Hirofumi Kai

doi:10.1016/j.jphs.2015.09.006

Structural stabilization of transthyretin by a new compound, 6-benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione

Takeshi Yokoyama, Shun Takaki, Keisuke Chosa, Takashi Sato, Mary Ann Suico, Yuriko Teranishi, Tsuyoshi Shuto, Mineyuki Mizuguchi^*, Hirofumi Kai

^*この論文の責任著者

構造生物学研究室

研究成果: ジャーナルへの寄稿 › 学術論文 › 査読

5 被引用数 (Scopus)

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Familial amyloid polyneuropathy (FAP) is a genetic, adult-onset, neurodegenerative disorder caused by amyloid formation of transthyretin (TTR), a thyroxine-binding protein. Mutation in TTR causes a propensity of TTR tetramer to dissociate to monomer, which is the first step to amyloidosis. Thus, a drug that can stabilize the tetramer structure will have therapeutic benefit. Here, by virtual screening and biochemical assays, we identified small molecule 6-benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione (L6) that can prevent the dissociation of TTR to monomer. X-ray crystallography reveals that L6 binds to the T4 binding pocket of TTR. These findings show that L6 is a candidate TTR stabilizer.

本文言語	英語
ページ（範囲）	240-243
ページ数	4
ジャーナル	Journal of Pharmacological Sciences
巻	129
号	4
DOI	https://doi.org/10.1016/j.jphs.2015.09.006
出版ステータス	出版済み - 2015/12

ASJC Scopus 主題領域

分子医療
薬理学

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10.1016/j.jphs.2015.09.006

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title = "Structural stabilization of transthyretin by a new compound, 6-benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione",

abstract = "Familial amyloid polyneuropathy (FAP) is a genetic, adult-onset, neurodegenerative disorder caused by amyloid formation of transthyretin (TTR), a thyroxine-binding protein. Mutation in TTR causes a propensity of TTR tetramer to dissociate to monomer, which is the first step to amyloidosis. Thus, a drug that can stabilize the tetramer structure will have therapeutic benefit. Here, by virtual screening and biochemical assays, we identified small molecule 6-benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione (L6) that can prevent the dissociation of TTR to monomer. X-ray crystallography reveals that L6 binds to the T4 binding pocket of TTR. These findings show that L6 is a candidate TTR stabilizer.",

keywords = "6-Benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione (L6), Familial amyloid polyneuropathy (FAP), Transthyretin (TTR)",

author = "Takeshi Yokoyama and Shun Takaki and Keisuke Chosa and Takashi Sato and Suico, {Mary Ann} and Yuriko Teranishi and Tsuyoshi Shuto and Mineyuki Mizuguchi and Hirofumi Kai",

note = "Publisher Copyright: {\textcopyright} 2015 Japanese Pharmacological Society.",

year = "2015",

month = dec,

doi = "10.1016/j.jphs.2015.09.006",

language = "英語",

volume = "129",

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AU - Yokoyama, Takeshi

AU - Takaki, Shun

AU - Chosa, Keisuke

AU - Sato, Takashi

AU - Suico, Mary Ann

AU - Teranishi, Yuriko

AU - Shuto, Tsuyoshi

AU - Mizuguchi, Mineyuki

AU - Kai, Hirofumi

PY - 2015/12

Y1 - 2015/12

N2 - Familial amyloid polyneuropathy (FAP) is a genetic, adult-onset, neurodegenerative disorder caused by amyloid formation of transthyretin (TTR), a thyroxine-binding protein. Mutation in TTR causes a propensity of TTR tetramer to dissociate to monomer, which is the first step to amyloidosis. Thus, a drug that can stabilize the tetramer structure will have therapeutic benefit. Here, by virtual screening and biochemical assays, we identified small molecule 6-benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione (L6) that can prevent the dissociation of TTR to monomer. X-ray crystallography reveals that L6 binds to the T4 binding pocket of TTR. These findings show that L6 is a candidate TTR stabilizer.

AB - Familial amyloid polyneuropathy (FAP) is a genetic, adult-onset, neurodegenerative disorder caused by amyloid formation of transthyretin (TTR), a thyroxine-binding protein. Mutation in TTR causes a propensity of TTR tetramer to dissociate to monomer, which is the first step to amyloidosis. Thus, a drug that can stabilize the tetramer structure will have therapeutic benefit. Here, by virtual screening and biochemical assays, we identified small molecule 6-benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione (L6) that can prevent the dissociation of TTR to monomer. X-ray crystallography reveals that L6 binds to the T4 binding pocket of TTR. These findings show that L6 is a candidate TTR stabilizer.

KW - 6-Benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione (L6)

KW - Familial amyloid polyneuropathy (FAP)

KW - Transthyretin (TTR)

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DO - 10.1016/j.jphs.2015.09.006

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SN - 1347-8613

VL - 129

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Structural stabilization of transthyretin by a new compound, 6-benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione

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