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

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。

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.