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.
authors.affiliation: Faculty of Pharmaceutical Sciences, University of Toyama, Toyama 930-0914, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yokoyama
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Takaki
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Chosa
authors.affiliation: Department of Analytical and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Suico
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Teranishi
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shuto
authors.affiliation: Faculty of Pharmaceutical Sciences, University of Toyama, Toyama 930-0914, Japan. Electronic address: mineyuki@pha.u-toyama.ac.jp.
authors.forename: Mineyuki
authors.initials: M
authors.lastname: Mizuguchi
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan. Electronic address: hirokai@gpo.kumamoto-u.ac.jp.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kai
mesh_terms: D000682:Amyloid; D028227:Amyloid Neuropathies, Familial / Q000188:drug therapy* / Q000235:genetics*; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D042822:Genomic Instability / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use*; D007546:Isoquinolines / Q000494:pharmacology* / Q000627:therapeutic use*; D058990:Molecular Targeted Therapy; D009154:Mutation; D053644:Naphthalimides / Q000494:pharmacology* / Q000627:therapeutic use*; D058105:Polymerization; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics*; D011485:Protein Binding; D013974:Thyroxine
chemical_list: C000610973:6-benzoyl-2-hydroxy-1H-benzo(de)isoquinoline-1,3(2H)-dione; D000682:Amyloid; D006877:Hydroxamic Acids; D007546:Isoquinolines; D053644:Naphthalimides; D011228:Prealbumin; D013974:Thyroxine
keywords: 6-Benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione (L6); Familial amyloid polyneuropathy (FAP); Transthyretin (TTR)