title: Cyclodextrin, a novel therapeutic tool for suppressing amyloidogenic transthyretin misfolding in transthyretin-related amyloidosis.
abstract: TTR (transthyretin), a β-sheet-rich protein, is the precursor protein of familial amyloidotic polyneuropathy and senile systemic amyloidosis. Although it has been widely accepted that protein misfolding of the monomeric form of TTR is a rate-limiting step for amyloid formation, no effective therapy targeting this misfolding step is available. In the present study, we focused on CyDs (cyclodextrins), cyclic oligosaccharides composed of glucose units, and reported the inhibitory effect of CyDs on TTR amyloid formation. Of various branched β-CyDs, GUG-β-CyD [6-O-α-(4-O-α-D-glucuronyl)-D-glucosyl-β-CyD] showed potent inhibition of TTR amyloid formation. Far-UV CD spectra analysis showed that GUG-β-CyD reduced the conformational change of TTR in the process of amyloid formation. In addition, tryptophan fluorescence and 1H-NMR spectroscopy analyses indicated that GUG-β-CyD stabilized the TTR conformation via interaction with the hydrophobic amino acids of TTR, especially tryptophan. Moreover, GUG-β-CyD exerted its inhibitory effect by reducing TTR deposition in transgenic rats possessing a human variant TTR gene in vivo. Collectively, these results 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, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
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: 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: D058227:Amyloidogenic Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000686:Amyloidosis / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D003505:Cyclodextrins / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009844:Oligosaccharides / Q000494:pharmacology; D011228:Prealbumin / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding; D051381:Rats; D055647:Rats, Transgenic; D014364:Tryptophan / Q000235:genetics / Q000378:metabolism
chemical_list: D058227:Amyloidogenic Proteins; D003505:Cyclodextrins; D009844:Oligosaccharides; D011228:Prealbumin; C438085:cyclomaltoheptaosyl-(6-1)-glucopyranosyl-(4-1)-glucopyranosiduronic acid; D014364:Tryptophan