RXP 407, a phosphinic peptide, is a potent inhibitor of angiotensin I converting enzyme able to differentiate between its two active sites

Dive, Vincent; Cotton, J. P.; Yiotakis, Athanasios; Michaud, Annie; Vassiliou, Stamatia; Jiráček, Jiřı́; Vazeux, Gilles; Chauvet, M.T.; Cuniasse, Philippe; Corvol, Pierre

doi:10.1073/pnas.96.8.4330

Cited by 171 publications

(199 citation statements)

References 36 publications

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“…195 One of the bradykinin potentiator peptides, BPPb, was shown to be 300-fold more C-selective, 200 and the phosphinic tetrapeptide RXPA380 is 3000-fold more C-selective. 190 However, BPP-12b is 30-fold more N-selective, and the phosphinic tetrapeptide RXP407 is 1000-fold more N-selective [201][202][203] (Figure 3).…”

Section: Future Of Aceismentioning

confidence: 99%

Reinventing the ACE inhibitors: some old and new implications of ACE inhibition

2009

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Since their inception, angiotensin-converting enzyme (ACE) inhibitors have been used as first-line therapy for the treatment of cardiovascular and renal diseases. They restore the balance between the vasoconstrictive salt-retentive and hypertrophy-causing peptide angiotensin II (Ang II) and bradykinin, a vasodilatory and natriuretic peptide. As ACE is a promiscuous enzyme, ACE inhibitors alter the metabolism of a number of other vasoactive substances. ACE inhibitors decrease systemic vascular resistance without increasing heart rate and promote natriuresis. They have been proven effective in the treatment of hypertension, and reduce mortality in congestive heart failure and left ventricular dysfunction after myocardial infarction. They inhibit ischemic events and stabilize plaques. Furthermore, they delay the progression of diabetic nephropathy and neuropathy and act as antioxidants. Ongoing studies have elucidated protective roles for them in both memory-related disorders and cancer. INTRODUCTIONIn recent years, stressful and fiercely competitive lifestyles and food habits have compounded the problems of hypertension. Long-standing and stressful, progressively rising hypertension can lead to many disorders, including myocardial infarction (MI), cerebrovascular events, congestive heart failure, peripheral arterial insufficiency, premature mortality 1 and renal dysfunction leading to glomerulosclerosis and kidney artery aneurysm. 2 A number of therapies are available, but angiotensin-converting enzyme (ACE) inhibitors have been the preferred first-line therapy for hypertension, congestive heart failure, left ventricular (LV) systolic dysfunction and MI. 3,4 ACE inhibitors (ACEis) have been in use for the past two decades, and the interest in them is still growing. Recently, the discovery of domain-selective ACEis and new members of the renin-angiotensin system (RAS) (that is, angiotensin-converting enzyme 2) have again fueled the interest of researchers. Some new studies have expanded the already impressive clinical profile of ACEis. This review traces some already known and new facets of ACE inhibition and introduces new advances in the designing of a new generation of ACEis.

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Section: Future Of Aceismentioning

confidence: 99%

Reinventing the ACE inhibitors: some old and new implications of ACE inhibition

2009

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“…The expression and purification of ACE were performed as previously described (Wei et al, 1991) and was kindly provided by Pierre Corvol (Institut National de la Santé et de la Recherche Médicale, Paris, France). Mca-Ala-Ser-Asp-Lys-N3(2,4-dinitrophenyl)L-2,3-diaminopropionyl (Mca-Ala) and Mca-Ser-Asp-Lys-N3(2,4-dinitrophenyl)L-2,3-diaminopropionyl (Mca-Ser) were prepared following the procedure previously described (Dive et al, 1999). BPP-7a (PyroGlu-Asp-Gly-Pro-Ile-Pro-Pro-OH), BPP-10c (PyroGlu-Asn-TrpPro-His-Pro-Gln-Ile-Pro-Pro-OH), bradykinin, captopril, angiotensin I, and angiotensin II were purchased from Bachem Bioscience (King of Prussia, PA).…”

Section: Drugsmentioning

confidence: 99%

Do the Cardiovascular Effects of Angiotensin-Converting Enzyme (ACE) I Involve ACE-Independent Mechanisms? New Insights from Proline-Rich Peptides ofBothrops jararaca

Ianzer

Santos²,

Etelvino³

et al. 2007

J Pharmacol Exp Ther

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Angiotensin-converting enzyme (ACE) inhibitors were developed based on proline-rich oligopeptides found in the venom of Bothrops jararaca (Bj) previously known as bradykinin-potentiating peptides (BPPs). However, the exact mechanism of action of BPPs remains unclear. The role of the ACE in the cardiovascular effects of two of naturally proline-rich oligopeptides (Bj-BPP-7a and Bj-BPP-10c) was evaluated in vitro and in vivo. Bj-BPP-7a does not potentiate the cardiovascular response to bradykinin and is a weak inhibitor of ACE C and N sites (K i ϭ 40,000 and 70,000 nM, respectively), whereas Bj-BPP-10c is a strong bradykinin potentiator and inhibitor of the ACE C site (K i ϭ 0.5 versus 200 nM for N site). Strikingly, both peptides, in doses ranging from 0.47 to 71 nmol/kg, produced long-lasting reduction (Ͼ6 h) in the mean arterial pressure of conscious spontaneously hypertensive rats (maximal change, 45 Ϯ 6 and 53 Ϯ 6 mm Hg for Bj-BPP-7a and Bj-BPP-10c, respectively). The fall in blood pressure was accompanied by variable degrees of bradycardia. In keeping with the absence of relationship between ACE-inhibitory and antihypertensive activities, no changes in the pressor effect of angiotensin I or in the hypotensive effect of bradykinin were observed at the peak of the cardiovascular effects of both peptides. Our results indicate that the antihypertensive effect of two Bj-BPPs containing the motif Ile-Pro-Pro is unrelated to their ability for inhibiting ACE or potentiating bradykinin (BK), indicating as a major component ACE and BK-independent mechanisms. These results are in line with previous observations suggesting ACE inhibition-independent mechanisms for angiotensin I-converting enzyme inhibitor.

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“…18 Therefore, it is important to evaluate separately the inhibitory activity of any new ACE or ACE/NEP inhibitor on the 2 ACE domains. In this study, we report for the first time an in vitro and in vivo selective assessment of a dual NEP/ACE inhibitor, omapatrilat, and of a pure ACE inhibitor, fosinopril, in humans.…”

Section: Azizi Et Al Inhibition Of Active Sites Of Ace By Omapatrilatmentioning

confidence: 99%

In Vitro and In Vivo Inhibition of the 2 Active Sites of ACE by Omapatrilat, a Vasopeptidase Inhibitor

et al. 2000

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Abstract-The vasopeptidase inhibitor omapatrilat inhibits both neutral endopeptidase and angiotensin-converting enzyme (ACE). The in vitro and in vivo inhibitory potency of omapatrilat and the specific ACE inhibitor fosinopril toward the 2 active sites of ACE (called N-and C-domains) was investigated with the use of 3 substrates: angiotensin I, which is equally cleaved by the 2 ACE domains; hippuryl-histidyl-leucine, specific synthetic substrate of the C-domain in highsalt conditions; and a newly synthesized specific substrate of the N-domain designed by acetylating the lysine residue of AcSDKP. In vitro, omapatrilat was 5 times more potent than fosinoprilat in inhibiting angiotensin I hydrolysis. Omapatrilat inhibited similarly both N-and C-domain hydrolysis, whereas fosinoprilat was slightly more specific for the N-domain. The in vivo selective inhibitory potency of single oral doses of 10 mg omapatrilat and 20 mg fosinopril were investigated in a double-blind, placebo-controlled, cross-over study in 9 mildly sodium-depleted normotensive subjects. In accordance with the in vitro results, fosinopril appeared to be more specific for the N-domain than the C-domain in vivo, since plasma and urine AcSDKP concentrations were significantly higher than those observed with omapatrilat. This study shows that it is possible to assess separately in vitro and in vivo the selectivity of ACE or ACE/neutral endopeptidase inhibitors. A differential selectivity may explain some peculiar properties observed with some ACE inhibitors. Key Words: angiotensin-converting enzyme Ⅲ angiotensin-converting enzyme inhibitors Ⅲ AcSDKP Ⅲ human A ngiotensin-converting enzyme (ACE) has 2 distinct active catalytic sites, hereafter called the N-and C-domains. 1 The 2 domains of ACE have both common and different characteristics. Both sites hydrolyze angiotensin (Ang) I and bradykinin with almost the same catalytic efficiency. 2 The N-domain cleaves specifically 2 physiological substrates, Ang-(1-7) 3 and N-acetyl-seryl-aspartyl-lysylproline (AcSDKP), a hemoregulatory peptide. 4 There is no known specific physiological substrates of the C-domain, but the C-domain activity can be assessed specifically in vitro by the use of the synthetic tripeptide hippuryl-histidyl-leucine (HHL), because its hydrolysis in high chloride concentration depends mostly on this catalytic site. 1 Finally, some ACE inhibitors display different inhibitory potency toward the 2 active sites. 5 For example, captopril appears to be Ϸ16 times more efficient for blocking the N-domain than the C-domain, whereas lisinopril is equally potent toward the 2 active sites. 6 The inhibitory potency of ACE inhibitors toward ACE can be studied with the use of synthetic 7 and physiological substrates 8 or with the use of a competitive assay against radiolabeled ACE inhibitors. 9 In addition, it is possible to explore the characteristics of the inhibitors toward the 2 ACE domains separately by selecting appropriate substrates and markers. Such studies will allow us to specifically relate t...

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RXP 407, a phosphinic peptide, is a potent inhibitor of angiotensin I converting enzyme able to differentiate between its two active sites

Cited by 171 publications

References 36 publications

Reinventing the ACE inhibitors: some old and new implications of ACE inhibition

Reinventing the ACE inhibitors: some old and new implications of ACE inhibition

Do the Cardiovascular Effects of Angiotensin-Converting Enzyme (ACE) I Involve ACE-Independent Mechanisms? New Insights from Proline-Rich Peptides ofBothrops jararaca

In Vitro and In Vivo Inhibition of the 2 Active Sites of ACE by Omapatrilat, a Vasopeptidase Inhibitor

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