Structural stabilization of transthyretin by a new compound, 6-benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione

  • J Pharmacol Sci. 2015 Dec;129(4):240-3. doi: 10.1016/j.jphs.2015.09.006.
Takeshi Yokoyama  1 ,  Shun Takaki  2 ,  Keisuke Chosa  2 ,  Takashi Sato  3 ,  Mary Ann Suico  2 ,  Yuriko Teranishi  2 ,  Tsuyoshi Shuto  2 ,  Mineyuki Mizuguchi  4 ,  Hirofumi Kai  5
Affiliations
  • 1. Faculty of Pharmaceutical Sciences, University of Toyama, Toyama 930-0914, Japan.
  • 2. Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
  • 3. Department of Analytical and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
  • 4. Faculty of Pharmaceutical Sciences, University of Toyama, Toyama 930-0914, Japan. Electronic address: [email protected].
  • 5. Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan. Electronic address: [email protected].
PMID: 26639444 DOI: 10.1016/j.jphs.2015.09.006
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.

Keywords
6-Benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione (L6); Familial amyloid polyneuropathy (FAP); Transthyretin (TTR).
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