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

通过化学生物学发现治疗阿尔茨海默病的机制药物

• 批准号: 19679001
• 负责人: TOMITA Taisuke
• 金额: $ 73.72万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (S)
• 财政年份: 2007
• 资助国家: 日本
• 起止时间: 2007 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-19679001/
• 关键词: 脳神経疾患; 薬学; 酵素; 生理活性; アルツハイマー; セクレターゼ; アミロイド; ケミカルバイオロジー; 構造解析

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.

γ-分泌酶是一种膜内蛋白酶，负责产生与阿尔茨海默病发病机制相关的淀粉样蛋白-β肽。因此，γ-分泌酶活性的调节是阿尔茨海默病的合理疗法。我们揭示了γ-分泌酶裂解的新的分子机制，并根据该机制合理设计了新型的γ-分泌酶抑制剂。这些发展为阿尔茨海默病的疾病修饰药物的开发提供了希望。

项目成果

BACE1 activity is modulated by cell-associated sphingosine-1-phosphate.

• DOI: 10.1523/jneurosci.6467-10.2011
• 发表时间: 2011-05-04
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Takasugi N;Sasaki T;Suzuki K;Osawa S;Isshiki H;Hori Y;Shimada N;Higo T;Yokoshima S;Fukuyama T;Lee VM;Trojanowski JQ;Tomita T;Iwatsubo T
• 通讯作者: Iwatsubo T

Comparison of Presenilin 1 and Presenilin 2 γ-Secretase Activities Using a Yeast Reconstitution System*

• DOI: 10.1074/jbc.m111.270108
• 发表时间: 2011-11
• 期刊: The Journal of Biological Chemistry
• 作者: Y. Yonemura;E. Futai;Sosuke Yagishita;S. Suo;T. Tomita;T. Iwatsubo;S. Ishiura

Single chain variable fragment against nicastrin inhibits the gamma-secretase activity.

针对尼卡斯特林的单链可变片段抑制γ-分泌酶活性。

• 发表时间: 2009
• 期刊: Journal of Biological Chemistry 284
• 作者: Hayashi I;Takatori S;Urano Y;et al
• 通讯作者: et al

BACE1 activity ismodulated by cell-associatedsphingosine-1-phosphate in neurons

BACE1 活性由神经元中细胞相关的 1-磷酸鞘氨醇调节

• 发表时间: 2011
• 期刊: J Neurosci
• 影响因子: 5.3
• 作者: 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
• 通讯作者: Iwatsubo T

Structure and function relationship of the β- and γ-secretases toward development of treatment of Alzheimer disease

β-和γ-分泌酶的结构和功能关系与阿尔茨海默病治疗发展的关系

• 发表时间: 2011
• 作者: Nishino;K.;A.Yamaguchi.;Taisuke Tomita
• 通讯作者: Taisuke Tomita