Development of drugs targeting secretory inhibition of transthyretin for familial amyloidotic polyneuropathy

2013 Fiscal Year Final Research Report

• Project/Area Number: 24790079
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: Kumamoto University
• Principal Investigator: SATO Takashi 熊本大学, 発生医学研究所, 特定事業研究員 (70555755)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Keywords: トランスサイレチン / アミロイド / 小胞体 / 小胞体関連分解 / 化合物スクリーニング / 薬理学

Research Abstract

The final goal of this study is to develop drug for treatment of Transthyretin (TTR)-Familial Amyloidotic Polyneuropathy (FAP). We previously identified that inhibition of TTR tetramerization in the endoplasmic reticulum that blocks secretion of mutant TTR could be a target of candidate drug for treatment of FAP. In this study, we performed in silico virtual screening of inhibitor for TTR tetramerization. Among 2.5 million compound, we selected about 20 compounds and examined the effect of selected compounds on secretion and tetramerization of mutant TTR. Finally, we identified 2 compounds that reduce secretion of mutant TTR, one of which inhibits tetramerization of mutant TTR. Moreover, to perform high-throughput screening of chemical libraries, we developed a fluorescence-based assay system that monitor TTR tetramerization in vitro and plan to use this system in future study.

Research Products

• [Journal Article] Inhibition of post-translational N-glycosylation by HRD1 that controls the fate of ABCG5/8 transporter (2014)
  • Author(s): Suzuki S, Shuto T, Sato T, Kaneko M, Takada T, Suico MA, Cyr DM, Suzuki H, Kai H
  • Journal Title: Sci Rep Volume: 3 Pages: 4258
  • DOI: 10.1038/srep04258.
  • Peer Reviewed
• [Journal Article] Insulin receptor activation through its accumulation in lipid rafts by mild electrical stress (2013)
  • Author(s): Morino-Koga S, Yano S, Kondo T, Shimauchi Y, Matsuyama S, Okamoto Y, Suico MA,Koga T, Sato T, Shuto T, Arima H, Wada I, Araki E, Kai H
  • Journal Title: J Cell Physiol Volume: 228(2) Pages: 439-46
  • DOI: 10.1002/jcp.24149.
  • Peer Reviewed
• [Journal Article] STT3B-Dependent Posttranslational N-Glycosylation as a Surveillance System for Secretory Protein (2012)
  • Author(s): Sato T, Sako Y, Sho M, Momohara M, Suico MA, Shuto T, Nishitoh H, Okiyoneda T, Kokame K, Kaneko M, Taura M, Miyata M, Chosa K,Koga T, Morino-Koga S, Wada I, Kai H
  • Journal Title: Mol Cell Volume: 47(1) Pages: 99-110
  • DOI: 10.1016/j.molcel.2012.04.015.
  • Peer Reviewed
• [Journal Article] Mild electrical stimulation and heat shock ameliorates progressive proteinuria and renal inflammation in mouse model of Alport syndrome (2012)
  • Author(s): Koga T, Kai Y, Fukuda R, Morino-Koga S, Suico MA, Koyama K, Sato T, Shuto T, Kai H
  • Journal Title: PLoS One Volume: 7(8) Pages: 43852
  • DOI: 10.1371/journal.pone.0043852.
  • Peer Reviewed
• [Presentation] The endoplasmic reticulum-oriented drug development for familial amyloid polyneuropathy (2013)
  • Author(s): Chosa K, Yamakawa R, Sato T, Yokoyama T, Mizuguchi M, Suico MA, Shuto T, Kai H
  • Organizer: ASCB Annual Meeting
  • Place of Presentation: New Orleans, USA
  • Year and Date: 20131214-18
• [Presentation] The endoplasmic reticulum-oriented drug development for transthyretin familial amyloid polyneuropathy. IXth International Symposium on Familial Amyloidotic (2013)
  • Author(s): Chosa K, Yamakawa R, Sato T, Yokoyama T, Mizuguchi M, Suico MA, Shuto T, Kai H
  • Organizer: Polyneuropathy
  • Place of Presentation: Rio de Janeiro, Brazil
  • Year and Date: 20131110-13
• [Presentation] 翻訳後N型糖鎖修飾を介した小胞体品質管理機構による家族性アミロイドーシスの発症性制御機構の解明 (2013)
  • Author(s): 佐藤卓史,庄美里,スイコメリーアン,首藤剛,甲斐広文
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
  • Year and Date: 20130327-30
• [Presentation] 異常な構造を持つ分泌タンパク質の新たな小胞体品質管理機構 (2013)
  • Author(s): 庄美里,佐藤卓史,帖佐圭佑,山川瑠斐子,スイコメリーアン,首藤剛,甲斐広文
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡
  • Year and Date: 20130321-23
• [Presentation] 変異トランスサイレチンの翻訳後N型糖鎖修飾の意義とその制御因子の探索 (2012)
  • Author(s): 庄美里,佐藤卓史,西頭英起,小亀浩市,金子雅幸,和田郁夫,メリーアンスイコ,首藤剛,甲斐広文
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡
  • Year and Date: 20121214-16
• [Presentation] 変異トランスサイレチンの翻訳後N型糖鎖修飾の意義とその制御因子の探索 (2012)
  • Author(s): 庄美里,佐藤卓史,スイコメリーアン,首藤剛,和田郁夫,甲斐広文
  • Organizer: 第29回日本薬学会九州支部大会
  • Place of Presentation: 熊本
  • Year and Date: 20121208-09
• [Presentation] STT3B-dependent posttranslational N-glycosylation as a surveillance system for secretory protein (2012)
  • Author(s): Kai H, Sato T, Sho M, Sako Y, Suico MA, Shuto T
  • Organizer: Quality Control From Molecules to Organelles
  • Place of Presentation: Heidelberg, Germany
  • Year and Date: 20120919-22
• [Remarks] 熊本日日新聞 医療QQ「特定酵素「STT3B」、異常タンパク質を分解熊大グループが新たな仕組み発見」 平成24年7月20日
  • URL: http://qq.kumanichi.com/medical/2012/07/post-1996.php
• [Remarks] 熊本大学プレスリリース 「細胞内の異常なタンパク質を取り除く,新しいメカニズムを発見」 平成24年7月13日
  • URL: http://www.kumamoto-u.ac.jp/daigakujouhou/kouhou/pressrelease/2012_file/release120713.pdf