Drug discovery for Familial amyloid polyneuropathy (FAP), an incurable hereditary disease

• Project/Area Number: 25253012
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pharmacology in pharmacy
• Research Institution: Kumamoto University
• Principal Investigator: KAI HIROFUMI 熊本大学, 大学院生命科学研究部, 教授 (30194658)
• Co-Investigator(Kenkyū-buntansha): SHUTO Tsuyoshi 熊本大学, 大学院生命科学研究部(薬学系), 准教授 (80333524) ; SUICO Mary Ann Soten 熊本大学, 大学院生命科学研究部(薬学系), 助教 (20363525)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥47,450,000 (Direct Cost: ¥36,500,000、Indirect Cost: ¥10,950,000); Fiscal Year 2015: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000); Fiscal Year 2014: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000); Fiscal Year 2013: ¥29,510,000 (Direct Cost: ¥22,700,000、Indirect Cost: ¥6,810,000)
• Keywords: 化合物ライブラリースクリーニング / 家族性アミロイドポリニューロパチー / アミロイドーシス / トランスサイレチン

Outline of Final Research Achievements

Familial amyloid polyneuropathy (FAP) is one of the hereditary amyloidoses caused by a point mutation in the human plasma protein, transthyretin (TTR). Amyloid fibrils derived from TTR variants accumulate in peripheral nerves and visceral organs, leading to inflammation-associated failure of multiple organs. TTR variants are easily dissociated from tetramer to monomer, which is the first step to amyloidosis, due to the low energetic stability of TTR variant tetrameric structure in comparison with wild-type (WT) TTR. We aimed to determine novel drugs that could either stabilize extracellular TTR tetramer or inhibit TTR secretion from the cells by high-throughput screening (HTS). Here, Western blotting- and Thioflavin-based biochemical assays identified thirteen compounds that stabilize the TTR tetramer as well as two TTR amyloid-solubilizing agents, and one inhibitor of TTR secretion from the cells were identified in this study.

Research Products

• [Journal Article] TALENs Facilitate Single-step Seamless SDF Correction of F508del CFTR in Airway Epithelial Submucosal Gland Cell-derived CF-iPSCs. (2016)
  • Author(s): Suzuki S, Sargent RG, Illek B, Fischer H, Esmaeili-Shandiz A, Yezzi MJ, Lee A, Yang Y, Kim S, Renz P, Qi Z, Yu J, Muench MO, Beyer AI, Guimaraes AO, Ye L, Chang J, Fine EJ, Cradick TJ, Bao G, Rahdar M, Porteus MH, Shuto T, Kai H, Kan YW, Gruenert DC
  • Journal Title: Molecular Therapy Nucleic Acids Volume: 5 Pages: e273-e273
  • DOI: 10.1038/mtna.2015.43
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The effect of mild electrical stimulation with heat shock on diabetic KKAy mice. (2015)
  • Author(s): Kai Y, Tsurekawa Y, Fukuda R, Omachi K, Piruzyan M, Okamoto Y, Motomura K, Suico MA, Shuto T, Kondo T, Araki E, Kai H.
  • Journal Title: Integr Mol Med. Volume: 3 Issue: 1 Pages: 473-477
  • DOI: 10.15761/imm.1000190
  • Peer Reviewed / Open Access
• [Journal Article] Structural stabilization of transthyretin by a new compound, 6-benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione (2015)
  • Author(s): Yokoyama T, Takaki S, Chosa K, Sato T, Suico MA, Teranishi Y, Shuto T, Mizuguchi M, Kai H
  • Journal Title: J Pharmacol Sci. Volume: 129 Issue: 4 Pages: 240-243
  • DOI: 10.1016/j.jphs.2015.09.006
  • Peer Reviewed / Open Access
• [Journal Article] 細胞内ストレスと生活習慣病-分子シャペロンHsp72の耐糖能改善効果とその機序- (2015)
  • Author(s): 荒木 栄一, 近藤 龍也, 甲斐 広文
  • Journal Title: 日本体質医学会雑誌 Volume: 77 Pages: 163-166
  • Peer Reviewed / Open Access
• [Journal Article] Endoplasmic Reticulum (ER) Stress Induces Sirtuin 1 (SIRT1) Expression via the PI3K-Akt-GSK3β Signaling Pathway and Promotes Hepatocellular Injury. (2015)
  • Author(s): Koga T, Suico MA, Shimasaki S, Watanabe E, Kai Y, Koyama K, Omachi K, Morino-Koga S, Sato T, Shuto T, Mori K, Hino S, Nakao M, Kai H.
  • Journal Title: J Biol Chem. Volume: 290 Issue: 51 Pages: 30366-30374
  • DOI: 10.1074/jbc.m115.664169
  • Peer Reviewed / Open Access
• [Journal Article] Preemptive quality control protects the ER from protein overload via the proximity of ERAD components and SRP. (2015)
  • Author(s): Kadowaki H, Nagai A, Maruyama T, Takami Y, Satrimafitrah P, Kato H, Honda A, Hatta T, Natsume T, Sato T, Kai H, Ichijo H, Nishitoh H
  • Journal Title: Cell reports Volume: 13 Issue: 5 Pages: 944-956
  • DOI: 10.1016/j.celrep.2015.09.047
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi. (2015)
  • Author(s): Susuki-Miyata S, Miyata M, Lee BC, Xu H, Kai H, Yan C, Li JD.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 112 Issue: 14
  • DOI: 10.1073/pnas.1418716112
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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: Scientific reports Volume: 4 Issue: 1 Pages: 4258-4258
  • DOI: 10.1038/srep04258
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of Three-Dimensional Cultured HepG2 Cells in a Nano Culture Plate System: an In Vitro Human Model of Acetaminophen Hepatotoxicity. (2013)
  • Author(s): Kohei Aritomi, Yoichi Ishitsuka, Yoshiro Tomishima, Daisuke Shimizu, Nazuki Abe, Tsuyoshi Shuto, Mitsuru Irikura, Hirofumi Kai, and Tetsumi Irie.
  • Journal Title: J Pharmacpl Sci. Volume: 124 Pages: 218-229
  • NAID: 130003391476
  • Peer Reviewed
• [Journal Article] Inhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD (2013)
  • Author(s): Komatsu K
  • Journal Title: Nature Communications Volume: 4 Issue: 1 Pages: 1684-1684
  • DOI: 10.1038/ncomms2674
  • Peer Reviewed
• [Journal Article] Mild electrical stimulation at 0.1-ms pulse width induces p53 protein phosphorylation and G2 arrest in human epithelial cells. (2013)
  • Author(s): Fukuda ft, Suico MA, Koyama K, Omachi K, Kai Y, Matsuyama S, Mitsutake K, Taura M, Mo rino-Koga S, Shuto T, Kai H.
  • Journal Title: Journal of Biological Chemistry Volume: 288(22) Issue: 22 Pages: 16117-16126
  • DOI: 10.1074/jbc.m112.442442
  • Peer Reviewed
• [Presentation] 遺伝性疾患患者由来iPS細胞を用いた遺伝子治療と再生医療；遺伝性呼吸器疾患嚢胞性繊維症(Cystic Fibrosis, CF)患者由来iPS細胞のゲノム修復及び機能的気道上皮細胞への分化誘導 (2016)
  • Author(s): 鈴木 伸悟、R. Geoffrey Sargent、帖佐 圭佑、Beate Illek、Horst Fischer、Alaleh Eamaeili-Shandiz、首藤 剛、甲斐 広文、Yuet. W Kan、Dieter.C Gruenert
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜（神奈川）
  • Year and Date: 2016-03-09
• [Presentation] Molecular mechanism of the intracellular quality control of TTR by Hsp47 (2015)
  • Author(s): Y. Wakita, R. Yamakawa, K. Chosa, S. Takaki, Y. Teranishi, T. Sato, M.Suico, T. Shuto, H. Kai
  • Organizer: 2015 cell biology ascb annual meeting
  • Place of Presentation: San Diego(USA)
  • Year and Date: 2015-12-12
  • Int'l Joint Research
• [Presentation] Hsp47によるTTRタンパク質の細胞内品質管理機構の解明 (2015)
  • Author(s): 脇田 有梨子、山川 瑠斐子、帖佐 圭佑、高木 舜、寺西 ゆり子、佐藤 卓史、Mary Ann Suico、首藤 剛、甲斐 広文
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド（兵庫）
  • Year and Date: 2015-12-01
• [Presentation] Hsp47によるTTRタンパク質の細胞内品質管理機構の解明 (2015)
  • Author(s): 脇田 有梨子、山川 瑠斐子、帖佐 圭佑、高木 舜、寺西 ゆり子、佐藤 卓史、Mary Ann Suico、首藤 剛、甲斐 広文
  • Organizer: 第32回日本薬学会九州支部大会
  • Place of Presentation: 九州保健福祉大学（宮崎）
  • Year and Date: 2015-11-28
• [Presentation] バーチャルスクリーニングシステムを活用した、家族性アミロイドポリニューロパチー原因タンパク質 TTR の四量体安定化剤の同定 (2015)
  • Author(s): 高木 舜、帖佐 圭佑、横山 武司、佐藤 卓史、Mary Ann Suico、寺西 ゆり子、首藤 剛、水口 峰之、甲斐 広文
  • Organizer: 第37回生体膜と薬物の相互作用シンポジウム2015
  • Place of Presentation: 熊本大学薬学部（熊本）
  • Year and Date: 2015-11-19
• [Presentation] Hsp47によるTTRタンパク質の細胞内品質管理機構の解明 (2015)
  • Author(s): 脇田 有梨子、山川 瑠斐子、帖佐 圭佑、高木 舜、寺西 ゆり子、佐藤 卓史、Mary Ann Suico、首藤 剛、甲斐 広文
  • Organizer: 第37回生体膜と薬物の相互作用シンポジウム2015
  • Place of Presentation: 熊本大学薬学部（熊本）
  • Year and Date: 2015-11-19
• [Presentation] 6-benzoyl-2-hydroxy-1H-benzo[de]isoquin oline-1,3(2H)-dione is a novel transthyretin stabilizer for familial amyloid polyneuropathy (2015)
  • Author(s): S. Takaki, K. Chosa, T. Yokoyama, Y. Teranishi, Y. Wakita, T. Sato, M. Suico, T. Shuto, M. Mizuguchi, H. Kai
  • Organizer: International Symposium on Chronic Inflammatory Diseases, Kumamoto (ISCIDK2015)
  • Place of Presentation: 熊本大学（熊本）
  • Year and Date: 2015-10-16
  • Int'l Joint Research
• [Presentation] High throughput screening-based identification of transthyretin stabilizers for familial amyloid polyneuropathy (2015)
  • Author(s): Y. Teranishi, K. Chosa, T. Shuto, S. Takaki, Y. Wakita, T. Sato, M. Suico, T. Yamashita, H. Kai
  • Organizer: International Symposium on Chronic Inflammatory Diseases, Kumamoto (ISCIDK2015)
  • Place of Presentation: 熊本大学（熊本）
  • Year and Date: 2015-10-16
  • Int'l Joint Research
• [Presentation] The molecular quality control of TTR by Hsp47 (2015)
  • Author(s): Y. Wakita, R. Yamakawa, K. Chosa, S. Takaki, Y. Teranishi, T. Sato, S. Ann, T. Shuto, H. Kai
  • Organizer: International Symposium on Chronic Inflammatory Diseases, Kumamoto (ISCIDK2015)
  • Place of Presentation: 熊本大学（熊本）
  • Year and Date: 2015-10-16
  • Int'l Joint Research
• [Presentation] 遺伝性腎炎Alport症候群の病態進行抑制因子および原因タンパク質に焦点を当てた新規治療薬の開発 (2015)
  • Author(s): 大町 紘平, 福田 亮介, 嘉村 美里, 寺本 啓祐, 横田 翼, 本村 敬士, 山川 瑠斐子, Mary Ann Suico, 首藤 剛, 甲斐 広文
  • Organizer: 第6回分子腎臓フォーラム
  • Place of Presentation: グランフロント大阪（大阪）
  • Year and Date: 2015-09-05
• [Presentation] Characterization of the intracellular behavior of COL4A5 and clarification of molecular mechanism of alport syndrome (2015)
  • Author(s): K. Omachi, M. Kamura, K. Teramoto, R. Fukuda, M. Suico, T. Shuto, H. Kai
  • Organizer: 52nd ERA-EDTA CONGRESS LONDON 2015
  • Place of Presentation: London（UK）
  • Year and Date: 2015-05-28
  • Int'l Joint Research
• [Presentation] Screening of small compounds to develop endoplasmic reticulum-oriented drug for familial amyloid polyneuropathy. (2014)
  • Author(s): K. Chosa, S. Takaki, R. Yamakawa, Y. Wakita, Y. Teranishi, T. Sato, T. Yokoyama, M. Mizuguchi, M. Suico, T. Shuto, H. Kai
  • Organizer: The 2014 ascb/ifcb Meeting
  • Place of Presentation: Philadelphia（USA）
  • Year and Date: 2014-12-06 – 2014-12-10
• [Presentation] 小胞体品質管理機構を標的とした家族性アミロイドポリニューロパチー（FAP）の新規治療薬開発 (2014)
  • Author(s): 帖佐 圭佑, 高木 舜, 山川 瑠斐子, 脇田 有梨子, 寺西 ゆり子, 佐藤 卓史, 横山 武司, 水口 峰之, Mary Ann Suico , 首藤 剛, 甲斐 広文
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] バーチャルおよびハイスループットスクリーニングを用いた家族性アミロイドポリニューロパチーの新規治療薬の開発 (2014)
  • Author(s): 帖佐 圭佑, 高木 舜, 脇田 有梨子, 寺西 ゆり子, 山川 瑠斐子, 佐藤 卓史, 横山 武司, 水口 峰之, Mary Ann Suico , 首藤 剛, 甲斐 広文
  • Organizer: 第8回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 熊本大学薬学部（熊本県熊本市）
  • Year and Date: 2014-11-15 – 2014-11-16
• [Presentation] The endoplasmic reticulum-oriented drug development for familial amyloid polyneuropathy (2014)
  • Author(s): K. Chosa, R. Yamakawa, T. Sato, T. Yokoyama, M. Mizuguchi, M. Suico, T. Shuto, H. Kai
  • Organizer: WCP2014 17th World Congress of Basic & Clinical Pharmacology
  • Place of Presentation: Cape Town（South Africa）
  • Year and Date: 2014-07-13 – 2014-07-18
• [Presentation] The endoplasmic reticulum-oriented drug development for familial amyloid polyneuropathy (2013)
  • Author(s): K. Chosa, R. Yamakawa, T. Sato, T. Yokoyama, M. Mizuguchi, M. Suico, T. Shuto, H. Kai
  • Organizer: 2013 ASCB Annual Meeting
  • Place of Presentation: The New Orleans Ernest N. Morial Convention Center, New Orleans, Lousiana,USA
• [Presentation] The endoplasmic reticulum-oriented drug development for transthyretin familial amyloid polyneuropathy (2013)
  • Author(s): Keisuke Chosa , Ruiko Yamakawa , Takashi Sato , Takeshi Yokoyama , Mineyuki Mizuguchi , Mary Ann Suico ,Tsuyoshi Shuto , Hirofumi Kai
  • Organizer: IXth International Symposium on Familial Amyloidotic Polyneuropathy
  • Place of Presentation: Auditorio do Centro de Convencoes Antonio Seabra Moggi,Rio de Janeiro, Brazil
• [Remarks] 熊本大学大学院薬学教育部 遺伝子機能応用学研究室
  • URL: http://molmed730.org/index.html
• [Remarks] 熊本大学大学院薬学教育部 遺伝子機能応用学研究室
  • URL: http://molmed730.org/index.html