Potent new inhibitors of human renin

Szelke, M.; Leckie, Brenda J.; Hallett, Allan; Jones, D.; Sueiras, J.E.; Atrash, Butrus; Lever, A. F.

doi:10.1038/299555a0

Cited by 247 publications

(94 citation statements)

References 20 publications

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“…Pepstatin derivatives such as lactoyl-pepstatin have Ki values ranging from 4 x 10-10 to 6 x 10-6 M towards human pepsin and gastricsin respectively (Valler et al, 1985a). Similarly, synthetic peptide inhibitors of renin containing statine (Boger et al, 1983) or other non-hydrolysable analogues (Szelke et al, 1982;Hallett et al, 1985), although they do display very effective inhibition of human renin (Ki values approx. 10-9-010 M), nevertheless demonstrate weaker interactions (approx.…”

Section: Methodsmentioning

confidence: 99%

The selectivity of action of the aspartic-proteinase inhibitor IA3 from yeast (Saccharomyces cerevisiae)

Dreyer¹,

Valler²,

Kay³

et al. 1985

Biochemical Journal

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The ability of the aspartic-proteinase inhibitor IA3 from yeast (Saccharomyces cerevisiae) to affect the activities of a range of mammalian and microbial aspartic proteinases was examined. The inhibitor appeared to be completely selective in that only the aspartic proteinase A from yeast was inhibited to any significant extent. IA3 thus represents the first example of a totally specific, naturally occurring, aspartic-proteinase inhibitor.

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Section: Methodsmentioning

confidence: 99%

The selectivity of action of the aspartic-proteinase inhibitor IA3 from yeast (Saccharomyces cerevisiae)

Dreyer¹,

Valler²,

Kay³

et al. 1985

Biochemical Journal

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“…60,61 On the other hand, this renin inhibitor did not blunt bindings of renin and prorenin to (P)RR, whereas it significantly decreased the mRNA expression of (P)RR in the kidney cortex of diabetic hypertensive Ren2 rats. 61 A peptide like renin inhibitor was first reported by Szelke et al 62 Peptides derived from the bovine pepsinogen (17 residues at the NH 2 -terminus of bovine and 1-16 residues of the porcine pepsinogens) were found to inhibit pepsin activity in a milk clotting assay at pH 5.5 with high values of K i . 63,64 Cumin et al 65 demonstrated that a peptide which is located in the region corresponding to 9-20 in human renin prosegment inhibited the renin activity.…”

Section: Effects Of Aliskiren Hrp/decoy and 'Hinge' Peptides On Renimentioning

confidence: 99%

Biochemical properties of renin and prorenin binding to the (pro)renin receptor

Nabi

Suzuki

2009

Hypertens Res

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The discovery of (pro)renin receptor, (P)RR, has made the renin-angiotensin system (RAS) more multifaceted. Interaction of renin and prorenin with this receptor has set a new perspective about the physiological functions, activation mechanism and pathophysiological roles of renin/prorenin. Uses of peptides mimicking the structure of the ligands have been very effective for determining structure-function relationship between the ligands and receptor. The probable pivotal role of decoy peptide region (R 10P IFLKRMPSI 19P ) of prorenin prosegment was suggested for higher binding affinity of prorenin to (P)RR than that of mature renin. Recently, 'hinge' region peptide (S 149 QGVLKEDVF 158 ) in renin/prorenin molecule has been reported. Both renin and prorenin can interact with (P)RR through the 'hinge' region. Furthermore, it has been proposed that prorenin has multiple binding sites whereas renin has a single binding site for (P)RR. To comprehend the activation mechanism of renin and prorenin after receptor binding, it is very important to understand their interaction with the receptor. Several kinds of peptides designed from the regions of the tertiary structure of renin and predicted model of prorenin facilitated the study of the in vitro binding mechanisms for renin and prorenin to (P)RR. Here, a series of recent in vitro studies was reviewed to discuss a possible binding mechanism of renin/prorenin to the (P)RR.

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“…4,31,32 The renin assay can be adapted to inhibitor screening by diluting renin serially on a xed mixture of peptidic substrate and competitive inhibitor, incubating for 90 min at 37 C, and detecting the proteolytic reaction on an antibody-coated microtiter plate. The inhibition of renin can then be analyzed based on the integrated Michaelis-Menten equation for competitive inhibition: …”

Section: Inhibition Of Reninmentioning

confidence: 99%

Kinetic analysis of renin and its inhibitors by detecting double-labelled peptidic substrates with an immunoassay

Gorris

2013

Analyst

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The proteolytic activity of renin is a key element in the regulation of blood pressure and a main target for inhibitor design. Currently, the activity of renin and its inhibitors is mainly analyzed using radioimmunoassays or FRET-substrates, which both have their limitations. Here, a novel kinetic assay is presented that combines the advantages of a homogeneous proteolytic reaction and a robust heterogeneous detection in a sandwich immunoassay format. The proteolysis in solution is not influenced by surface interactions and yields accurate kinetic values, while the specific detection of the cleavage products on a microtiter plate strongly reduces interference by concomitant substances and allows for a self-referenced signal readout. A new enzyme kinetic scheme for the inhibition of renin has been developed and validated by using the model inhibitor pepstatin. This kinetic analysis is amenable to parallelization for large-scale inhibitor screening. Furthermore, it can be easily adapted to inhibitors of other medically important proteases.

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Potent new inhibitors of human renin

Cited by 247 publications

References 20 publications

The selectivity of action of the aspartic-proteinase inhibitor IA3 from yeast (Saccharomyces cerevisiae)

The selectivity of action of the aspartic-proteinase inhibitor IA3 from yeast (Saccharomyces cerevisiae)

Biochemical properties of renin and prorenin binding to the (pro)renin receptor

Kinetic analysis of renin and its inhibitors by detecting double-labelled peptidic substrates with an immunoassay

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