Divergent synthesis of multifunctional molecular probes to elucidate the enzyme specificity of dipeptidic γ-secretase inhibitors
Divergent synthesis of multifunctional molecular probes to elucidate the enzyme specificity of dipeptidic γ-secretase inhibitors
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DOI：
10.1021/cb700073y
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发表时间：
2007-06-01
影响因子：
4
通讯作者：
Iwatsubo, Takeshi
中科院分区：
文献类型：
--
作者：
Fuwa, Haruhiko;Takahashi, Yasuko;Iwatsubo, Takeshi
基于己内酰胺衍生的二肽分泌酶抑制剂（GSI）、化合物E（CE）和LY 411575类似物（DBZ）的多功能分子探针的发散合成通过Cu（I）催化的叠氮化物/炔融合反应有效地完成。光亲和标记实验，使用这些衍生物耦合到光活化和生物素部分提供了直接的证据表明，CE和DBZ的分子目标是早老素1的N-末端片段内的分泌酶复合物。而且，这些光探针直接靶向信号肽肽酶。这些数据表明，分子探针的发散合成已成功地应用于表征GSI与其分子靶标的相互作用，并定义抑制剂与膜内裂解蛋白酶结合的结构要求。
Divergent synthesis of multifunctional molecular probes based on caprolactam-derived dipeptidic -secretase inhibitors (GSIs), Compound E (CE) and LY411575 analogue (DBZ), was efficiently accomplished by means of Cu(I)-catalyzed azide/alkyne fusion reaction. Photoaffinity labeling experiments using these derivatives coupled to photoactivatable and biotin moieties provided direct evidence that the molecular targets of CE and DBZ are the N-terminal fragment of presenilin 1 within the -secretase complex. Moreover, these photoprobes directly targeted signal peptide peptidase. These data suggest that the divergent synthesis of molecular probes has been successfully applied to characterize the interaction of GSIs with their molecular targets and define the structural requirements for inhibitor binding to intramembrane-cleaving proteases.