Targeted 纬-Secretase Inhibition To Control the Notch Pathway in Renal Diseases

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• 作者：Lucienne Juillerat-Jeanneret ; Alexander Flohr ; Manfred Schneider ; Isabelle Walter ; Jean-Christophe Wyss ; Rajesh Kumar ; Dela Golshayan ; Johannes D. Aebi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：October 22, 2015
• 年：2015
• 卷：58
• 期：20
• 页码：8097-8109
• 全文大小：565K
• ISSN：1520-4804

文摘

Notch is a membrane inserted protein activated by the membrane-inserted 纬-secretase proteolytic complex. The Notch pathway is a potential therapeutic target for the treatment of renal diseases but also controls the function of other cells, requiring cell-targeting of Notch antagonists. Toward selective targeting, we have developed the 纬-secretase inhibitor-based prodrugs 13a and 15a as substrates for 纬-glutamyltranspeptidase (纬-GT) and/or 纬-glutamylcyclotransferase (纬-GCT) as well as aminopeptidase A (APA), which are overexpressed in renal diseases, and have evaluated them in experimental in vitro and in vivo models. In nondiseased mice, the cleavage product from Ac-纬-Glu-纬-secretase inhibitor prodrug 13a (纬-GT-targeting and 纬-GCT-targeting) but not from Ac-伪-Glu-纬-secretase inhibitor prodrug 15a (APA-targeting) accumulated in kidneys when compared to blood and liver. Potential nephroprotective effects of the 纬-secretase inhibitor targeted prodrugs were investigated in vivo in a mouse model of acute kidney injury, demonstrating that the expression of Notch1 and cleaved Notch1 could be selectively down-regulated upon treatment with the Ac-纬-Glu-纬-secretase-inhibitor 13a.