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

Details

Serval ID
serval:BIB_E96F41E2C7E9
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Targeted γ-Secretase Inhibition To Control the Notch Pathway in Renal Diseases.
Journal
Journal of Medicinal Chemistry
Author(s)
Juillerat-Jeanneret L., Flohr A., Schneider M., Walter I., Wyss J.C., Kumar R., Golshayan D., Aebi J.D.
ISSN
1520-4804 (Electronic)
ISSN-L
0022-2623
Publication state
Published
Issued date
2015
Peer-reviewed
Oui
Volume
58
Number
20
Pages
8097-8109
Language
english
Notes
Publication types: Journal ArticlePublication Status: ppublish
Abstract
Notch is a membrane inserted protein activated by the membrane-inserted γ-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 γ-secretase inhibitor-based prodrugs 13a and 15a as substrates for γ-glutamyltranspeptidase (γ-GT) and/or γ-glutamylcyclotransferase (γ-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-γ-Glu-γ-secretase inhibitor prodrug 13a (γ-GT-targeting and γ-GCT-targeting) but not from Ac-α-Glu-γ-secretase inhibitor prodrug 15a (APA-targeting) accumulated in kidneys when compared to blood and liver. Potential nephroprotective effects of the γ-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-γ-Glu-γ-secretase-inhibitor 13a.
Pubmed
Web of science
Create date
24/11/2015 17:13
Last modification date
20/08/2019 16:12
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