Discovery for mechanism-based drugs for Alzheimer's disease by chemical biology

2011 Fiscal Year Final Research Report

• Project/Area Number: 19679001
• Research Category: Grant-in-Aid for Young Scientists (S)
• Allocation Type: Single-year Grants
• Research Field: Biological pharmacy
• Research Institution: The University of Tokyo
• Principal Investigator: TOMITA Taisuke 東京大学, 大学院・薬学系研究科, 准教授 (30292957)
• Project Period (FY): 2007 – 2011
• Keywords: 脳神経疾患 / 薬学 / 酵素 / 生理活性

Research Abstract

γ-Secretase is an intramembrane protease that is responsible for the generation of amyloid-βpeptide linked to the pathogenesis of Alzheimer disease. Thus, modulation ofγ-secretase activity is a plausible therapeutics for Alzheimer disease. We have unveiled the novel molecular mechanisms of theγ-secretase cleavage, and established the novelγ-secretase inhibitors by rational design based on the mechanism. These developments offer a promise for development of a disease-modifying drug for Alzheimer disease.

Research Products

• [Journal Article] Neutralizationof theγ-secretase activity bymonoclonal antibody againstextracellular domain of nicastrin (2012)
  • Author(s): Hayashi I, Takatori S, Urano Y, Miyake Y, Takagi J, Sakata-Yanagimoto M, Iwanari H, Osawa S, Morohashi Y, Li T, Wong PC, Chiba S, Kodama T, Hamakubo T, Tomita T, Iwatsubo T
  • Journal Title: Oncogene Volume: 31 Pages: 787-79
  • DOI: DOI:10.1038/onc.2011.265
  • Peer Reviewed
• [Journal Article] Phenylpiperidine-typeγ-secretasemodulators target the transmembranedomain 1 of presenilin 1 (2011)
  • Author(s): Ohki Y, Higo T, Uemura K, Shimada N, Osawa S, Funamoto S, Ihara Y, Berezovska O, Yokoshima S, Fukuyama T, Tomita T, Iwatsubo T
  • Journal Title: EMBO J Volume: 30 Pages: 4815-24
  • DOI: DOI:10.1038/emboj.2011.372
  • Peer Reviewed
• [Journal Article] BACE1 activity ismodulated by cell-associatedsphingosine-1-phosphate in neurons (2011)
  • Author(s): Takasugi N, Sasaki T, Suzuki K, Osawa S, Isshiki H, Hori Y, Shimada N, Higo T, Yokoshima S, Fukuyama T, Lee VMY, Trojanowski JQ, Tomita T, Iwatsubo T
  • Journal Title: J Neurosci Volume: 31 Pages: 6850-6857
  • Peer Reviewed
• [Journal Article] Participation oftransmembrane domain 1 ofpresenilin 1 in the catalytic porestructure of theγ-secretase (2010)
  • Author(s): Takagi S, Tominaga A, Tomita T, Iwatsubo T
  • Journal Title: J Neurosci Volume: 30 Pages: 15943-15050
  • Peer Reviewed
• [Journal Article] Functionalanalysis of the transmembranedomains of presenilin 1 : PARTICIPATION OFTRANSMEMBRANE DOMAINS 2AND 6 IN THE FORMATION OFINITIAL SUBSTRATE-BINDINGSITE OFγ-SECRETASE (2010)
  • Author(s): Watanabe N, Takagi S, Tominaga A, Tomita T, Iwatsubo T
  • Journal Title: J Biol Chem Volume: 285 Pages: 19738-19746
  • Peer Reviewed
• [Journal Article] Single chain variable fragmentagainst Nicastrin inhibits theγ-secretase activity (2009)
  • Author(s): Hayashi I, Takatori S, Urano Y Iwanari H, Isoo N, Osawa S, FukudaMA, Kodama T, Hamakubo T, Li T, Wong PC, Tomita T, Iwatsubo T
  • Journal Title: J Biol Chem Volume: 284 Pages: 27838-27847
  • Peer Reviewed
• [Journal Article] Inhibition of gamma-secretaseactivity by helical beta-peptidefoldamers (2009)
  • Author(s): Imamura Y, Watanabe N, Umezawa N, Iwatsubo T, Kato N, Tomita T, Higuchi T
  • Journal Title: J Am Chem Soc Volume: 131 Pages: 7353-7359
  • Peer Reviewed
• [Journal Article] Secretase inhibitors andmodulators for Alzheimer's diseasetreatment (2009)
  • Author(s): Tomita T
  • Journal Title: Expert RevNeurotherapeutics Volume: 5 Pages: 661-679
  • Peer Reviewed
• [Journal Article] The C-terminal PAL motif andtransmembrane domain 9 ofPresenilin 1 are involved in theformation of the catalytic pore of thegamma-secretase (2008)
  • Author(s): Sato C, Takagi S, Tomita T, IwatsuboT
  • Journal Title: J Neurosci Volume: 28 Pages: 6264-6271
  • Peer Reviewed
• [Journal Article] Divergent synthesis ofmultifunctional molecular probes toelucidate the enzyme specificity ofdipeptidic gamma-secretase inhibitors (2007)
  • Author(s): Fuwa H, Konno Y, Takahashi Y, Sasaki M, Yokoshima S, Kan T, Fukuyama T, Natsugari H, Tomita T, Iwatsubo T
  • Journal Title: ACS Chem Biol Volume: 2 Pages: 408-418
  • Peer Reviewed
• [Presentation] Structure and functionrelationship of theυ-and-secretasestoward development of treatment ofAlzheimer disease (2011)
  • Author(s): Tomita T
  • Organizer: 7th Fabisch-Symposium for Cancer Research and Molecular Cell Biology : Regulated Intramembrane Proteolysisin Cancer Development and Neurodegenerative Diseases
  • Place of Presentation: Potsdam, Germany
  • Year and Date: 20111005-07
• [Presentation] Structure-functionrelationship ofγ-secretase (2011)
  • Author(s): Tomita T
  • Organizer: 2011 International Conference on Molecular Neurodegeneration
  • Place of Presentation: Shanghai, China
  • Year and Date: 20110922-24
• [Presentation] Alzheimer Drug Mechanisms (2010)
  • Author(s): Tomita T
  • Organizer: 2010 FIP Pharmaceutical Science World Congress(PSWC)/AAPS
  • Place of Presentation: New Orleans, Louisiana, USA
  • Year and Date: 2010-09-18
• [Presentation] Molecular mechanism of action ofγ-secretase in hibitors and modulators (2010)
  • Author(s): Tomita T
  • Organizer: AAICAD2010
  • Place of Presentation: Honolulu, Hawaii, USA
  • Year and Date: 2010-07-12
• [Presentation] Structure and function relationship of theγ-secretase towarddevelopment of treatment of Alzheimer disease (2009)
  • Author(s): Tomita T
  • Organizer: International Proteolysis Society 2009
  • Place of Presentation: Gold Coast, Australia
  • Year and Date: 2009-10-28
• [Book] アルツハイマー病治療薬創出に向けたγセクレターゼの構造解析と機能制御蛋白質核酸酵素 (2009)
  • Author(s): 富田泰輔
  • Total Pages: 1684-1689
• [Remarks]
  • URL: http://www.f.u-tokyo.ac.jp/~neuropsc/index.html
• [Patent(Industrial Property Rights)] γセクレターゼ活性調節因子 (2009)
  • Inventor(s): 富田泰輔ら
  • Industrial Property Rights Holder: 東京大学
  • Industrial Property Number: 特願、2009-277604
  • Filing Date: 2009-12-07
• [Patent(Industrial Property Rights)] アルツハイマー病および癌の治療薬 (2009)
  • Inventor(s): 富田泰輔
  • Industrial Property Rights Holder: 東京大学
  • Industrial Property Number: PCT、JP2007/000438
  • Acquisition Date: 2009-04-25