title: Potential use of glucuronylglucosyl-β-cyclodextrin as a novel therapeutic tool for familial amyloidotic polyneuropathy.
abstract: Transthyretin (TTR)-related familial amyloidotic polyneuropathy, which is induced by amyloidogenic transthyretin (ATTR), is characterized by systemic accumulation of amyloid fibrils. Although it is believed that protein misfolding of monomeric form of TTR is a rate-limiting step for TTR amyloid formation, no effective therapy targeting this misfolding step is available. Our recent studies revealed that cyclodextrins (CyDs), cyclic oligosaccharides composed of glucose units, might interact with TTR and prevent the protein misfolding. In this study, we focused on and elucidated the inhibitory effect of 6-O-α-(4-O-α-D-Glucuronyl)-D-glucosyl-β-CyD (GUG-β-CyD) on TTR amyloid formation. Tryptophan (Trp) fluorescence and (1)H-NMR spectroscopy analyses indicated that GUG-β-CyD stabilized TTR conformation via interaction with the hydrophobic amino acids of TTR. Moreover, GUG-β-CyD suppressed TTR deposition in transgenic rats possessing a human ATTR V30M gene in vivo. Collectively, these data indicate that GUG-β-CyD may inhibit TTR misfolding by stabilizing its conformation, which, in turn, suppresses TTR amyloid formation.
authors.affiliation: Department of Diagnostic Medicine, Kumamoto University, Kumamoto, Japan. hjono@fc.kuh.kumamoto-u.ac.jp
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Jono
authors.forename: Takayuki
authors.initials: T
authors.lastname: Anno
authors.forename: Keiichi
authors.initials: K
authors.lastname: Motoyama
authors.forename: Yohei
authors.initials: Y
authors.lastname: Misumi
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Tasaki
authors.forename: Toshinori
authors.initials: T
authors.lastname: Oshima
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Mori
authors.forename: Mineyuki
authors.initials: M
authors.lastname: Mizuguchi
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Ueda
authors.forename: Satoru
authors.initials: S
authors.lastname: Shinriki
authors.forename: Makoto
authors.initials: M
authors.lastname: Shono
authors.forename: Konen
authors.initials: K
authors.lastname: Obayashi
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Arima
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ando
mesh_terms: D028227:Amyloid Neuropathies, Familial / Q000188:drug therapy* / Q000378:metabolism*; D000818:Animals; D006801:Humans; D008962:Models, Theoretical; D009844:Oligosaccharides / Q000378:metabolism* / Q000627:therapeutic use*; D011228:Prealbumin / Q000378:metabolism*; D017510:Protein Folding / Q000187:drug effects; D051381:Rats; D055647:Rats, Transgenic
chemical_list: D009844:Oligosaccharides; D011228:Prealbumin; C438085:cyclomaltoheptaosyl-(6-1)-glucopyranosyl-(4-1)-glucopyranosiduronic acid