AD治疗新药物——γ-分泌酶抑制剂

家族性阿尔采末病属常染色体显性遗传 ,其中大部分与编码早老素的基因发生突变所导致的γ 分泌酶功能异常有关 ,γ 分泌酶是一包括PS二聚体、Nicastrin、PEN 2等组分的多酶复合体。γ 分泌酶剪切APP、Notch、E cadherin、ErbB 4受体酪氨酸激酶等膜蛋白。目前已发现了许多类型的γ 分泌酶抑制剂 :基于二氟酮、二氟乙醇基团的γ 分泌酶抑制剂 ;脲多肽模拟化合物 ;基于羟乙基二肽电子等配体的化合物 ;具有α 螺旋结构的小肽 ;具有 4 氯 异香豆素基本母核的非肽抑制剂 ;含有丙氨酰基团的化合物。但这些抑制剂目前大多还只是作为一种工具药来研究γ 分泌酶的结构、功能以及作用机制。其中选择性抑制Aβ生成的γ 分泌酶抑制剂很有希望成为一种高效的阿尔采末病治疗药物

Promising drugs to treat Alzheimers disease--γ-secretase inhibitors

Mutations in presenilins caused most of the autosomal dominant familial forms of Alzheimers disease by altering γ secretase activity. The γ secretase is a large multiprotein complex including presenilin heterodimers,nicastrin,PEN 2 and additional unidentified components.γ secretase cleaves beta amyloid precursor protein,Notch,E cadherin,ErbB 4 receptor tyrosine kinase and other membrane proteins.The development of various γ secretase inhibitors not only provides a tool for investigating the structure, function and mechanism of γ secretase,but also presents a therapeutic strategy to slow progression of Alzheimers disease pathology. Threre are various classes of γ secretase inhibitors: compounds containing a difluoro ketone or a difluoro alcohol group, (hydroxyethy) urea peptidomimetics,compounds possessing a hydroxyethylene dipeptide isostere, short helical peptides, non peptidic inhibitors derived from 4 chloro isocoumarin synthon, compounds containing alanyl moiety.Among these species of γ secretase inhibitors,those which selectively affect Abeta production are especially the most promising drugs to treat Alzheimers disease.