Inhibition of angiotensin converting enzyme by the metalloendopeptidase 3.4.24.15 inhibitor c-phenylpropyl-alanyl-alanyl-phenylalanyl-p-aminobenzoate

Chappell, Mark C.; Welches, W R; Brosnihan, K. Bridget; Ferrario, Carlos M.

doi:10.1016/0196-9781(92)90053-6

Cited by 21 publications

(17 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Finally, intravenous infusion of CPP-AAF-pAB rapidly slowed down the arterial pressure of normotensive rats (34), indicating that 24-15 could play a role in the control of the pressor response in mammals. However, these data are still controversial since it was recently reported that CPP-AAF-pAB could undergo proteolytic cleavage (35)(36)(37). This produces a catabolite that potently inhibits angiotensinconverting enzyme, whose role in blood pressure response has been well documented.…”

Section: Discussionmentioning

confidence: 99%

Development of Highly Potent and Selective Phosphinic Peptide Inhibitors of Zinc Endopeptidase 24-15 Using Combinatorial Chemistry

Jiráček

Yiotakis

Vincent

et al. 1995

Journal of Biological Chemistry

113

View full text Add to dashboard Cite

This new inhibitor should be useful in assessing the contribution of this proteolytic activity in the physiological inactivation of neuropeptides known to be hydrolyzed, at least in vitro, by endopeptidase 24-15. Our study also demonstrates that the combinatorial chemistry approach leading to the development of phosphinic peptide libraries is a powerful strategy for discovering highly potent and selective inhibitors of zinc metalloproteases and should find a broader application in studies of this important class of enzymes.The endopeptidase 24-15 (EC 3.4.24.15) 1 belongs to the zinc metalloprotease family (1) and resembles a peptidase previously purified from rabbit brain by Camargo et al. (2). Later, endopeptidase 24-15 was named thimet oligopeptidase with respect to the thiol and metal dependence of its catalytic activity (3-5). Molecular cloning of the cDNA of endopeptidase 24-15 revealed a HEXXH motif, which characterizes peptidases belonging to this family, and a cysteine residue, lying on the C-terminal side of the second histidine of the zinc binding motif (6). This cysteine residue has been proposed to be responsible for activation of the enzyme by 2-mercaptoethanol or dithiothreitol, as well as for inhibition of the enzyme activity by thiol reactive reagents (6).24-15 displays several biochemical and physicochemical properties (for a review, see Ref. 7) in common with another zinc-containing metallopeptidase, endopeptidase . Interestingly, these two peptidases have the ability to hydrolyze numerous bioactive or synthetic peptides at the same cleavage site, suggesting that they have a closely related active site (7-9).We previously reported that phosphodiepryl03, a phosphonamide peptide, acts as a potent mixed inhibitor of 24-15 and 24-16, with K i values in the nanomolar range (10). This inhibitor was shown to be unable to block the activity of several other zinc peptidases such as endopeptidase 24-11, angiotensin-converting enzyme, aminopeptidase M, leucine aminopeptidase, and carboxypeptidases A and B. We particularly studied the effect of this inhibitor in vivo on the neurotensin catabolism, since we previously established that 24-15 and 24-16 participated in vitro in the inactivation of this neuropeptide (11,12). We established that phosphodiepryl03 prevented neurotensin degradation in vivo in vascularly perfused dog ileum (13). More recently, several phosphodiepryl03 analogues were also proved to be potent but still acting as mixed inhibitors of

show abstract

Section: Discussionmentioning

confidence: 99%

Development of Highly Potent and Selective Phosphinic Peptide Inhibitors of Zinc Endopeptidase 24-15 Using Combinatorial Chemistry

Jiráček

Yiotakis

Vincent

et al. 1995

Journal of Biological Chemistry

113

View full text Add to dashboard Cite

show abstract

“…6 ' 7 Taken together, these data suggest that MEP-24.15 is a peptidase implicated in the metabolism of vasoactive peptides in vivo, and as such contributes to the control of circulatory hemostasis. However, Chappell et al 8 recently reported that in vitro cFP-AAF-pAB inhibits purified ACE with a K { of 0.2 imol/L and also competitively inhibits serum ACE activity. Cardozo and Orlowski (unpublished observation) found that in vitro cFP-AAF-pAB at concentrations of up to 10 jimol/L failed to inhibit ACE if an inhibitor of MEP-24.11 was added to the incubation medium.…”

Section: Mep-2415 Was First Identified By Orlowski Et Almentioning

confidence: 99%

“…In preliminary studies, 6 - 7 we found that cFP-AAF-pAB lowers MBP and increases cardiac output, renal blood flow (RBF), and plasma kinins. A recent report 8 states that in vitro cFP-AAF-pAB competitively inhibits purified angiotensin converting enzyme (ACE) with a K, of 0.2 fimo\[L and also inhibits serum ACE activity. This could be due to conversion of cFP-AAF-pAB to N-[l-(fl,S)-carboxyl-3-phenylpropyl]-Ala-Ala (cFP-AA), a compound having ACE inhibitory activity, by MEP-24.11 2 (enkephalinase) (Cardozo and Orlowski, unpublished observations).…”

mentioning

confidence: 99%

Effects of a metalloendopeptidase-24.15. Inhibitor on renal hemodynamics and function in rats.

Yang¹,

Saitoh²,

Scicli³

et al. 1994

Hypertension

View full text Add to dashboard Cite

/v"-[l-(ft.S)-carboxyl-3-phenylpropyl]-Ala-Ala-Phep-aminobenzoate (cFP-AAF-pAB), an active-site-directed inhibitor of metalloendopeptidase-24.15, has been shown to lower blood pressure, increase cardiac output and renal blood flow, and potentiate the intravenous bradykinin-induced vasodepressor response. Because in vivo cFP-AAF-pAB can be converted to A41-(R,S)-carboxyl-3-phenylpropyl]-Ala-Ala (a compound with angiotensin converting enzyme inhibitory activity) by metalloendopeptidase-24.11, it is possible that some of its effects are due to angiotensin converting enzyme inhibition. In the present study, we questioned (1) whether cFP-AAF-pAB inhibits angiotensin converting enzyme in vivo and (2) whether cFP-AAF-pAB has renal effects that are independent of its conversion to an angiotensin converting enzyme inhibitor. cFP-AAF-pAB alone (3 junol in 300 pL per rat) almost abolished the blood pressure response to angiotensin I, suggesting that in vivo it inhibits angiotensin converting enzyme. In rats pretreated with a high dose of enalaprilat (1 mg/kg), cFP-AAFpAB had no further effect on blood pressure, renal blood flow, or potentiation of the vasodepressor response to bradykinin but still increased glomerular filtration rate by 44±9% (P<.01); urine volume increased by 118±10% (P<.001), urinary sodium excretion by 230±31% (P<.001), urinary potassium excretion by 68±14% (P<.01), and urinary cyclic GMP by 55±18% (P<.01). All of these changes were significant compared with enalaprilat/vehicle-treated rats. Fractional excretion of sodium and potassium did not differ from controls. These results suggest that effects of cFP-AAF-pAB on blood pressure, renal blood flow, and potentiation of the vasodepressor response to bradykinin could be mediated by angiotensin converting enzyme inhibition. However, some of the renal effects may be due to inhibition of metalloendopeptidase-24.15 or peptidases other than angiotensin converting enzyme. Zn 2+ -containing neutral endopeptidase that is highly concentrated in the brain and testes but is also found in the kidney, heart, lung, and liver. 13In vitro, it degrades a variety of peptides such as bradykinin, angiotensin I (Ang I), neurotensin, and luteinizing hormone-releasing hormone (LHRH) and converts enkephalin-containing peptides into Leu-and Met-enkephalin.2 -4 In vivo, 7V-[l-(7?,S)-carboxyl-3-phenylpropylj-Ala-Ala-Phe-p-aminobenzoate (cFP-AAFpAB) blocks degradation of LHRH (a substrate for MEP-24.15); however, its physiological role in the metabolism of vasoactive peptides has not been determined. Genden and Molineaux 5 recently reported that inhibition of MEP-24.15 by cFP-AAF-pAB, an activesite-directed inhibitor, produced a marked fall in mean blood pressure (MBP) that was almost abolished by a kinin receptor antagonist. cFP-AAF-pAB also potentiated the bradykinin-induced vasodepressor response. In preliminary studies, lowers MBP and increases cardiac output, renal blood flow (RBF), and plasma kinins. A recent report 8 states that in vitro cFP-AAF-pAB competitively in...

show abstract

“…We have focussed our interests on a substrate-related inhibitor of EP 24.15, N-[l-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-paminobenzoate (cFP-AAY-pAB) (Chu & Orlowski, 1984;Orlowski et al, 1988). Although this compound, and its phenylalanine substituted analogue cFP-AAF-pAB are potent (Ki values of 16 and 27 nM respectively) and selective inhibitors of EP 24.15, they are unfortunately unstable in vivo, being broken down rapidly to produce N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala (cFP-AA), a potent inhibitor of angiotensin converting enzyme (ACE; E.C.3.4.15.1) (Lasdun et al, 1989;Chappell et al, 1992;Cardozo & Orlowski, 1993;Williams et al, 1993;Telford et al, 1995). The utility of these inhibitors as pharmacological tools for studying the physiology of EP 24.15 in vivo is thus limited by their short half life and the fact that experiments performed without concomitant inhibition of ACE are difficult to interpret.…”

Section: Introductionmentioning

confidence: 99%

Role of bradykinin receptors in the renal effects of inhibition of angiotensin converting enzyme and endopeptidases 24.11 and 24.15 in conscious rabbits

Tomoda

Lew

Smith

et al. 1996

British J Pharmacology

View full text Add to dashboard Cite

1 We tested the effects on systemic haemodynamics and renal function, of inhibition of endopeptidase (EP) 24.15 (E.C. 3.4.24.15), in conscious uninephrectomized rabbits in which the activities of angiotensin converting enzyme (ACE, E.C. 3.4.15.1) and neutral endopeptidase (EP 24.11, E.C. 3.4.24.11) were already inhibited. To test the role of bradykinin B2-receptors in mediating the effects following inhibition of these enzymes, the antagonist Hoe 140 was used. 2 Hoe 140 (0.1 mg kg-', i.v.) did not affect resting mean arterial pressure or heart rate, but antagonized the depressor effect of right atrial administration of bradykinin. The dose-response curve for bradykinin was shifted more than 1000 fold to the right for more than 4 h. Hoe 140 approximately doubled resting urine flow and increased fractional Na+ excretion from 4.2 to 6.0%; consistent with the hypothesis that it exerts a partial agonist effect on the kidney.3 Combined inhibition of ACE (captopril; 0.25 mg kg-' plus 0.2 mg kg-'h-') and EP 24.11 (SCH 39370; 3 mg kg-' plus 3 mg kg-'h-') was followed by a sustained reduction in arterial pressure (-6+ 2 mmHg) and increase in heart rate (35+7 beats min-'). There was a small increase in renal blood flow (by 6.5+3.2% relative to vehicle-treatment) without a change in glomerular filtration rate, and about a 150% increase in Na+ excretion. Hoe 140 (0.1 mg kg-', i.v.) pretreatment did not influence the renal effects of captopril and SCH 39370, although it did appear to blunt their hypotensive and tachycardic effects.4 When EP 24.15 was inhibited with N-[l-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP-AAY-pAB; 5 mg kg-' plus 3 mg kg-'h-', i.v.) in rabbits pretreated with captopril and SCH 39370, no changes in systemic haemodynamics or renal function were observed. 5 We concluded that in conscious uninephrectomized rabbits, EP 24.15 does not play a major role in modulating renal function, at least under conditions where ACE and EP 24.11 are already inhibited. In contrast, ACE and/or EP 24.11 do modulate renal function in this model, but their influences are mediated chiefly through metabolism of peptides other than bradykinin.

show abstract

Inhibition of angiotensin converting enzyme by the metalloendopeptidase 3.4.24.15 inhibitor c-phenylpropyl-alanyl-alanyl-phenylalanyl-p-aminobenzoate

Cited by 21 publications

References 12 publications

Development of Highly Potent and Selective Phosphinic Peptide Inhibitors of Zinc Endopeptidase 24-15 Using Combinatorial Chemistry

Development of Highly Potent and Selective Phosphinic Peptide Inhibitors of Zinc Endopeptidase 24-15 Using Combinatorial Chemistry

Effects of a metalloendopeptidase-24.15. Inhibitor on renal hemodynamics and function in rats.

Role of bradykinin receptors in the renal effects of inhibition of angiotensin converting enzyme and endopeptidases 24.11 and 24.15 in conscious rabbits

Contact Info

Product

Resources

About