title: S 17092-1, a highly potent, specific and cell permeant inhibitor of human proline endopeptidase.
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 Abeta. 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.
authors: IPMC du CNRS, UPR411, 660 Route des Lucioles, Valbonne, 06560, France.
authors: H
authors: H
authors: Barelli
authors: A
authors: A
authors: Petit
authors: E
authors: E
authors: Hirsch
authors: S
authors: S
authors: Wilk
authors: G
authors: G
authors: De Nanteuil
authors: P
authors: P
authors: Morain
authors: F
authors: F
authors: Checler
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D000626:Aminopeptidases / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000201:enzymology; D002154:Calpain / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002463:Cell Membrane Permeability; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D007211:Indoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D000085822:Prolyl Oligopeptidases; D012697:Serine Endopeptidases / Q000302:isolation & purification / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013379:Substrate Specificity; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D053778:Thiazolidines
chemical_list: D007211:Indoles; C118986:S 17092-1; D015842:Serine Proteinase Inhibitors; D013844:Thiazoles; D053778:Thiazolidines; D010450:Endopeptidases; D000626:Aminopeptidases; D007703:Peptidyl-Dipeptidase A; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases; D002154:Calpain