title: Discovery of γ-Mangostin as an Amyloidogenesis Inhibitor.
abstract: Transthyretin (TTR) is a homotetrameric protein involved in human hereditary amyloidoses. The discovery and development of small molecules that inhibit the amyloid fibril formation of TTR is one of the therapeutic strategies for these diseases. Herein, we discovered that γ-mangostin (γ-M) is an effective inhibitor against the amyloid fibril formation of V30M amyloidogenic TTR. In-vitro binding assays revealed that γ-M was the most potent of the selected xanthone derivatives, and it bound to the thyroxine (T4)-binding sites and stabilized the TTR tetramer. X-ray crystallographic analysis revealed the diagonal binding mode of γ-M and the two binding sites of chloride ions at the T4-binding site. One of the chloride ions was replaced with a water molecule in the α-mangostin complex, which is a methylated derivative of γ-M. The stronger inhibitory potency of γ-M could be explained by the additional hydrogen bonds with the chloride ion. The present study establishes γ-M as a novel inhibitor of TTR fibrillization.
authors: Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0914, Japan.
authors: Takeshi
authors: T
authors: Yokoyama
authors: Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors: Mitsuharu
authors: M
authors: Ueda
authors: Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors: Yukio
authors: Y
authors: Ando
authors: Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0914, Japan.
authors: Mineyuki
authors: M
authors: Mizuguchi
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D002712:Chlorides / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D007477:Ions; D044004:Xanthones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000682:Amyloid; D002712:Chlorides; D007477:Ions; D044004:Xanthones; C021053:mangostin