S 17092-1, a highly potent, specific and cell permeant inhibitor of human proline endopeptidase

Hélène Barelli, Agnès Petit, Etienne Hirsch, Sherwin Wilk, Guillaume De Nanteuil, Philippe Morain, Frédéric Checler

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56 Scopus citations

Abstract

Several lines of evidence indicate that proline endopeptidase (PE) could participate to the symptomatology and/or etiology of Alzheimer's disease. Thus, proline endopeptidase appears to contribute to the degradation of neuropeptides involved in learning and memory and could also control the production of the amyloidogenic peptide Aβ. Therefore the design of potent, selective and permeant inhibitors of human PE should lead to potential probes to assess the genuine contribution of this enzyme in Alzheimer's pathology. A novel perhydroindol carboxylic derivative, S17092-1 inhibits the hydrolysis of Z-Gly-Pro-7AMC-hydrolysing activity present in human brain nuclei with a high affinity (Ki = 1 nM) and behaves as a highly potent (Ki = 1.5 nM) inhibitor of partially purified human PE. By contrast, S17092-1 is unable to affect a series of other peptidases including aminopeptidases B and M, dipeptidylaminopeptidase IV, endopeptidases 3.4.24.11, 3.4.24.15, 3.4.24.16, calpains and angiotensin-converting enzyme. Furthermore, we show that the embryonic human kidney 293 cell line displays an intracellular PE-like activity that is blocked after preincubating cells with S17092-1, indicating that this inhibitor penetrates in HEK293 cells and could affect intracellular human PE. Altogether, we establish that S17092-1 behaves as a highly potent, specific and cell permeant inhibitor of human proline endopeptidase and can be seen as a probe to examine PE contribution in Alzheimer's disease.

Original languageEnglish
Pages (from-to)657-661
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume257
Issue number3
DOIs
StatePublished - 21 Apr 1999

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