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Updated: Jan 30, 2026
Genetic Analysis of Hereditary Transthyretin Ala97Ser Related Amyloidosis
Published on: June 9, 2018
Crown Ethers as Transthyretin Amyloidogenesis Inhibitors
Takeshi Yokoyama1, Mineyuki Mizuguchi1,2
1Faculty of Pharmaceutical Sciences , University of Toyama , 2630 Sugitani , Toyama 930-0914 , Japan.
Abstract:
Transthyretin (TTR) is a tetrameric protein found in human serum and associated with amyloid diseases. Because the tetramer dissociation and misfolding of the monomer precede amyloid fibril formation, development of a small molecule that binds to TTR and stabilizes the TTR tetramer is an efficient strategy for the treatment of amyloidosis. Here, we report our discovery of the anti-TTR amyloidogenesis activities of crown ethers. X-ray crystallographic analysis, binding assay, and chemical cross-linking assay showed that 4'-carboxybenzo-18C6 (4) stabilized the TTR tetramer by binding to the allosteric sites on the molecular surface of the TTR tetramer. In addition, 4 synergistically increased the stabilization activity of diflunisal, one of the most potent TTR amyloidogenesis inhibitors. These experimental evidences establish that 4 is a valuable template compound as an allosteric inhibitor of TTR amyloidogenesis.
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02:28Structure and Nomenclature of Ethers
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