Functional analysis of g-secretase, which concerned with generation of amiroide-b-pepilde1

与amiroide-b-pepilde1的生成有关的g-分泌酶的功能分析

• 批准号: 17590003
• 负责人: KAN Toshiyuki
• 金额: $ 1.86万
• 依托单位: University of Shizuoka
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590003/
• 关键词: γ-secretase; Alzheimer's disease; DAPT; photoaffinity probe; photoaffinity labeling; PS1 CTFs; familial AD; competing photolabeling; フォトアフィニティプローブ; 光親和性ラベリング; リガンド分子; 光反応性基; ビオチン; Ns-Strategy; βアミロイド産出; PS1CTF

We investigated the screening of a potent inhibitor and the functional analysis of y-secretase, which was identified as an important therapeutic target for Alzheimer's disease (AD). During the course of our investigation based on potent inhibitor DAPT (1), we developed a fitile synthetic method for a photoaffinity probe by utilizing the polymer-bound reagent. Furthermore, the utility of the reagent was demonstrated by synthesis of the probe and the photoaffinity labeling experiments of the probe clarified that the major direct target molecules for the DAPT are preseniline 1 C-terminal fragments (PS1 CTFs), which were discovered from the genetically investigation of familial AD. Additionally, a competing photolabeling experiment of the probe against various class of inhibitors, we dissected the inhibitory mechanism of DAPT.

我们研究了一个有效的抑制剂的筛选和γ-分泌酶的功能分析，这被确定为一个重要的治疗阿尔茨海默病（AD）的目标。在我们的研究过程中，基于有效的抑制剂DAPT（1），我们开发了一种利用聚合物结合试剂的光亲和探针的合成方法。此外，通过探针的合成和探针的光亲和标记实验证实了试剂的实用性，DAPT的主要直接靶分子是早老素1C末端片段（PS1 CTF），其是在家族性AD的遗传学研究中发现的。此外，我们还进行了DAPT探针与不同类型抑制剂的竞争性光标记实验，探讨了DAPT的抑制机制。

项目成果

Reaction behavior of cumulene on Diels-Alder and Friedel-Crafts reaction

积聚烯在 Diels-Alder 和 Friedel-Crafts 反应中的反应行为

• 发表时间: 2006
• 期刊: Chem.Lett. (In press)
• 作者: Asakawa;T.;Iinuma;M.;Furuta;T.;Fujii;S.;Kan;T.;Tanaka;K.
• 通讯作者: K.

Synthesis of biotinylated photoaffinity probes based on arylsulfonamide γ-secretase inhibitors

• DOI: 10.1016/j.bmcl.2006.05.091
• 发表时间: 2006-08-15
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
• 影响因子: 2.7
• 作者: Fuwa, Haruhiko;Hiromoto, Kenichi;Natsugari, Hideaki
• 通讯作者: Natsugari, Hideaki

Divergent Synthesis of Multifunctional Molecular Probes Enabled Elucidation of the Enzyme Specificity of Dipeptidic γ-Secretase Inhibitors on Presenilin-Type Aspartic Proteases

多功能分子探针的不同合成能够阐明二肽γ-分泌酶抑制剂对早老素型天冬氨酸蛋白酶的酶特异性

• 发表时间: 2007
• 期刊: ACS Chemical Biology 2
• 作者: 木越英夫(翻訳分担);富岡清(監訳);Tohru Fukuyama;Tohru Fukuyama;Tohru Fukuyama;Tohru Fukuyama
• 通讯作者: Tohru Fukuyama

Convenient synthesis of photoaffinity probes and evaluation of their cross-linking abilities

光亲和探针的便捷合成及其交联能力的评估

• 发表时间: 2007
• 期刊: Org lett 9
• 作者: Kan T^*;Kita Y;Morohashi Y;Tominari Y;Hosoda S;Tomita T;Natsugari H;Iwatsubo T;Fukuyama T
• 通讯作者: Fukuyama T