S 17092-1, a Highly Potent, Specific and Cell Permeant Inhibitor of Human Proline Endopeptidase

Barelli, Hélène; Petit, Agnès; Hirsch, Étienne C.; Wilk, Sherwin; Nanteuil, Guillaume De; Morain, Philippe; Checler, Frédéric

doi:10.1006/bbrc.1999.0366

Cited by 55 publications

(67 citation statements)

References 23 publications

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“…cannulated 1 wk before the i.c.v. infusion of S17092 (15). After overnight fasting, all mice were infused for 30 min with either S17092 (10 μM in saline containing 0.5% DMSO at a rate of 0.1 μL/min; Sigma catalog #SML0181) or the equivalent volume of vehicle.…”

Section: Methodsmentioning

confidence: 99%

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Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice

Kim¹,

Toda²,

D’Agostino³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Fig. 1. Bone cells express Avprs. Immunofluorescence micrographs (A) and Western immunoblotting (B)show the expression of Avpr1α in osteoblasts and osteoclasts, and as a function of osteoblast (mineralization) and osteoclast (with Rankl) differentiation. The expression of Avp (ligand) and Avpr1α (receptor) in osteoblasts is regulated by 17β-estradiol, as determined by quantitative PCR (C) and Western immunoblotting (D). (Magnification: A, 63×.) Because Avp is a small peptide, its precursor neurophysin II is measured. Statistics: Student t test, P values shown compared with 0 h. Stimulation of Erk phosphorylation (p-Erk) as a function of total Erk (t-Erk) by Avp (10 −8 M) in osteoclast precursors (preosteoclasts), osteoclasts (OC), and osteoblasts establishes functionality of the Avpr1α in the presence or absence of the receptor inhibitor SR49059 (10 −8 M) (E). Western immunoblotting showing the expression of Avpr2 in preosteoclasts, OCs (F), and osteoblasts (G) isolated from Avpr1α −/− mice, as well as in MC3T3.E1 osteoblast precursors (G). Functionality of Avpr2 was confirmed by the demonstration that cells from Avpr1α −/− mice remained responsive to AVP in reducing the expression of osteoblast differentiation genes, namely Runx2, Osx, Bsp, Atf4, Opn, and Osteocalcin (quantitative PCR, P values shown) (H). Only relevant bands from Western blots are shown, with gaps introduced where empty lanes are excised to conserve space.

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Section: Methodsmentioning

confidence: 99%

“…To determine the role of central PREP on glucose metabolism, next we infused i.c.v. a specific PREP inhibitor, S17092 (15), in WT mice and performed a GTT. Thirty minutes of infusion of S17092 in WT mice significantly increased glucose levels (Fig.…”

Section: (G) Pir/ir Ratio In the Hypothalamus Of Fedmentioning

confidence: 99%

Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice

Kim¹,

Toda²,

D’Agostino³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…28 Fmoc-Pro-PyrrCN (K i 5 nM) was also synthesized by S. Wilk; 21 contrary to Z-pro-prolinal, this is a reversible inhibitor that could easily be synthesized from commonly available intermediates using a simple 2-step procedure. S17092 (K i 1.5 nM) was developed by the Institut de Recherches Internationale Servier 22 and was described as a highly potent, specific, and cell-permeant inhibitor of proline endopeptidase. All of these inhibitors were tested for their capacity to block several other proteolytic enzymes at a concentration Ͼ1000-fold greater than their K i for POP, and all failed to do so.…”

Section: Discussionmentioning

confidence: 99%

“…Three different POPi were used: Z-prolyl-prolinal (Z-ProPro, Biomol), Fmoc-prolyl-pyrrolidine-2-nitrile (Fmoc-Pro-PyrrCN, a gift of S. Wilk, Mount Sinai School of Medicine, NY), 21 and S17092 (a gift of P. Vanhoutte, Institut de Recherches Internationales Servier, France). 22 Stock solutions of POPi were made with 20% DMSO, then diluted to their final concentration with water. POPi vehicle had the same percentage of DMSO.…”

Section: Effect Of Popi On Ac-sdkp Synthesis In Vitromentioning

confidence: 99%

Prolyl Oligopeptidase Is Involved in Release of the Antifibrotic Peptide Ac-SDKP

et al. 2004

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Abstract-N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a ubiquitous tetrapeptide hydrolyzed almost exclusively by angiotensin-converting enzyme (ACE). Chronic treatment with Ac-SDKP decreases cardiac and renal fibrosis and inflammatory cell infiltration in hypertensive rats. However, very little is known about endogenous synthesis of Ac-SDKP, except that thymosin-␤ 4 may be the most likely precursor. Two enzymes are potentially able to release Ac-SDKP from thymosin-␤ 4 : prolyl oligopeptidase (POP) and endoproteinase asp-N. POP is widely present and active in several tissues and biological fluids, whereas endoproteinase asp-N appears to be lacking in mammals. Therefore, we hypothesized that POP is the main enzyme involved in synthesizing the antifibrotic peptide Ac-SDKP. We investigated in vitro and in vivo production of Ac-SDKP. Using kidney cortex homogenates, we observed that Ac-SDKP was generated in a time-dependent manner in the presence of exogenous thymosin-␤ 4 , and this generation was significantly inhibited by several POP inhibitors (POPi), Z-prolyl-prolinal, Fmoc-prolyl-pyrrolidine-2-nitrile, and S17092. Long-term administration of S17092 in rats significantly decreased endogenous levels of Ac-SDKP in the plasma (from 1.76Ϯ0.2 to 1.01Ϯ0.1 nM), heart (from 2.31Ϯ0.21 to 0.83Ϯ0.09 pmol/mg protein), and kidneys (from 5.62Ϯ0.34 to 2.86Ϯ0.76 pmol/mg protein). As expected, ACE inhibitors significantly increased endogenous levels of Ac-SDKP in the plasma, heart, and kidney, whereas coadministration of POPi prevented this increase. We concluded that POP is the main enzyme responsible for synthesis of the antifibrotic peptide

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“…S 17092 is a highly potent, orally active, cell permeant inhibitor of proline endopeptidase in brain (Barelli et al 1999;Lepagnol et al 1996). S 17092 can at least partially reverse scopolamine-induced amnesia and age-associated spatial delayed alternation deficits in mice, as well as increase striatal substance P immunoreactivity (Lestage et al 1998).…”

Section: A Number Of Neuropeptides Are Affected In Parkinson's Diseasmentioning

confidence: 99%

Effects of the Prolyl Endopeptidase Inhibitor S 17092 on Cognitive Deficits in Chronic Low Dose MPTP-Treated Monkeys

Schneider

2002

Neuropsychopharmacology

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A number of neuropeptides are affected in Parkinson's disease and the enzyme proline endopeptidase contributes to the degradation of many of these neuropeptides, some of which are linked to a variety of cognitive functions. In the present study, the effects of the highly potent proline endopeptidase inhibitor S 17092 on cognitive deficits in monkeys induced by chronic low dose 2,3, It is generally recognized that non-demented Parkinson's disease (PD) patients exhibit a number of neuropsychological deficits, some of which are present even at the earliest stages of the disease (Lees and Smith 1983;Levin et al. 1989;Owen et al. 1993). Many of these deficits are 'frontal-like' in nature and consist of problems in attentional set shifting (Owen et al. 1993), distractibility (Sharpe 1990) planning and 'executive functions ' (Morris et al. 1988) and spatial working memory ). Parkinson's disease patients also may have difficulty performing a delayed matching-to-sample shortterm visual recognition memory task, but their problems appear more related to attentional difficulties rather than to visual recognition memory problems . The neurochemical deficits underlying the cognitive disturbances in PD patients are not completely known. While most of the motor symptoms of PD can be related to a nigrostriatal dopaminergic defect, the relationship between the dopaminergic defect and cognitive deficits in PD is less clear. Some cognitive deficits in PD may be dopa-responsive but others are not (Cooper et al. 1992;Lange et al. 1992). Some cognitive problems in PD patients are even exacerbated by dopaminergic therapy (Gotham et al. 1988). These findings suggest that the cognitive deficits in PD patients most likely arise from dysfunction of several cortical and subcortical neurotransmitter systems and functional circuits that cannot be normalized by dopamine replacement therapy alone. This is supported by the recent finding that a sub-type specific neuronal nicotinic acetylcholine receptor agonist, but not levodopa, was able to improve cognitive functioning in dopamine lesioned monkeys (Schneider et al. 1999). The nicotinic receptor agonist effects on cognition were most likely related to the ability of this compound to release dopamine from striatal, limbic and frontal cortical sites, norepinephrine from hippocampal, thalamic and frontal cortical sites and acetylcholine from various cortical and subcortical sites (Menzaghi et al. 1996;Sacaan et al. 1997).In addition to deficits in levels of various neurotransmitters in PD and in animal models of PD, decreased levels of various neuropeptides may also contribute to parkinsonian symptomatology (Mauborgne et al. 1983). Several neuropeptides, particularly substance P, have been implicated in learning and memory (Huston and Hasenohrl 1995) and are present endogenously in cortex and striatum. Substance P levels are also depleted in the striatum of monkeys made parkinsonian by exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Since proline-containing neuropep...

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S 17092-1, a Highly Potent, Specific and Cell Permeant Inhibitor of Human Proline Endopeptidase

Cited by 55 publications

References 23 publications

Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice

Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice

Prolyl Oligopeptidase Is Involved in Release of the Antifibrotic Peptide Ac-SDKP

Effects of the Prolyl Endopeptidase Inhibitor S 17092 on Cognitive Deficits in Chronic Low Dose MPTP-Treated Monkeys

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