Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new potent renin inhibitor, Iva-Phe-Nle-Sta-Ala-Sta-OH (SR 42128), and its arginine salt (SR 42128A) have been synthesized. This compound had a concentration required to displace 50% of ligand binding of 2.8 X 10(-8) M toward human plasma renin at pH 7.4 and was 2,000 times more potent than pepstatin. All primate renins tested were inhibited within the same order of magnitude whereas other animal renins were much less inhibited. The effect in vivo of SR 42128A was studied in sodium-depleted conscious monkeys. A single dose of SR 42128A produced a dose-dependent blood pressure decrease as well as a dose-dependent inhibition of plasma renin activity (PRA). Blood pressure was still significantly lowered 3 h after a single administration of 3 or 10 mg/kg whereas PRA was still completely inhibited. SR 42128 is a potent and long-acting tool for studying the role of the renin angiotensin system in primates and humans.
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PMID:In vitro and in vivo inhibition of human and primate renin by a new potent renin inhibitor: SR 42128. 241 15

Mean arterial blood pressure (MAP) was 100 +/- 4 mmHg in a group (n = 3) of conscious sodium-deficient dogs. A 3-day infusion of the renin inhibitor isovaleryl -His-Pro-Phe-His-Sta-Leu-Phe-NH2 (SCRIP) lowered MAP to an average of 79 +/- 4 mmHg. Termination of the infusion resulted in a prompt rise in MAP to 100 +/- 5 mmHg but plasma renin activity (PRA), which was 22 +/- 2 ng angiotensin (Ang) l/ml per h before the infusion, recovered only to 5 +/- 1 ng Ang l/ml per h during the same time (4 h after infusion). In other experiments in sodium-deficient dogs, a direct comparison was made between inhibition of PRA and the reduction of blood pressure. Over the dose range 0.1-2 micrograms/kg per min, PRA was inhibited in a dose-related manner, but MAP was not reduced. At dose levels beginning an order of magnitude higher (e.g. 20-160 g/kg per min), PRA was completely inhibited and there was a dose-related fall in MAP. These data suggest that there is no correlation between inhibition of PRA and the reduction in blood pressure in chronically sodium-deficient dogs. In other studies comparing renin inhibition with angiotensin converting enzyme (ACE) inhibition, there was evidence for greater efficacy of ACE inhibition in conscious sodium-deficient dogs, but no evidence of any difference in one-kidney, one clip hypertensive dogs.
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PMID:Characteristics of the blood pressure lowering action of renin inhibition and comparison with angiotensin converting enzyme inhibition. 266 14

Dipeptide and tripeptide derivatives containing a statine residue were synthesized as inhibitors of human renin. ES-305, bis[(1-naphthyl)methyl]acetyl(BNMA)-histidyl-statine 2(S)-methylbutylamide was found to be a highly potent inhibitor of human renin with a Ki value of 1.7 X 10(-9) M. Dipeptide derivatives with the BNMA group at the N-terminal (BNMA-Val-Sta-isoleucinol [ES-313], BNMA-Leu-Sta-isoleucinol [ES-316], and BNMA-Nle-Sta-isoleucinol [ES-317]) had potencies against human renin that were similar to the potency of ES-305. All these dipeptide derivatives competitively inhibited human renin. The inhibitors were also potent against monkey renin but were less effective against renins from pig, goat, dog, rabbit, and rat. ES-305 had little effect on cathepsin D and pepsin at the concentration of 10(-5) M. The other derivatives showed detectable inhibition of cathepsin D (IC50, 10(-6) - 10(-7) M) and pepsin (10(-5) - 10(-6) M). All the compounds had little or no effect on trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at the concentration of 10(-5) M. Our results indicate that ES-305 is a highly potent and specific inhibitor of human renin. This compound is superior to other, previously described statine-containing renin inhibitors with respect to molecular size and enzyme specificity.
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PMID:Statine-containing dipeptide and tripeptide inhibitors of human renin. 308 74

Two new inhibitors, 4 and 5, of the aspartic proteinase porcine pepsin were synthesized. These compounds, which span the P4-P'3 binding subsites of the enzyme, were derived by replacing the Nph-Phe dipeptidyl unit of a good pepsin substrate, H2N-Phe-Gly-His-Nph-Phe-Ala-Phe-OMe (3), with statine [(3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, Sta]. Hexapeptide 5, H2N-Phe-Gly-Val-(S,S)-Sta-Ala-Phe-OMe, is an extremely potent inhibitor of pepsin with a Ki value less than 1 nM. This result is consistent with the proposal that statine functions as a bioisosteric replacement for a substrate dipeptidyl unit. Compound 4, which contains His at P2, is 2 orders of magnitude less active than the valine analogue 5 (Ki = 150 nM). The factor for the decrease in binding to pepsin effected by replacement of Val by His at P2 parallels the ratio of protonated vs unprotonated imidazole group in peptide 4 at pH 4, according to the Henderson-Hasselbach equation. This result suggests that a positively charged side chain at P2 is undesirable for maximum pepsin inhibition. Kinetic constants for several known inhibitors of pepsin and renin are presented that demonstrate that the effect of His incorporation at P2 on pepsin inhibition depends upon the peptide sequence and that the effect is considerably different for renin inhibitors. We further suggest that the high selectivity of potent renin inhibitors known to be only weak pepsin and cathepsin D inhibitors is due in part to the extent of histidine protonation at P2 arising from pH differences in the inhibition kinetics assay of renin (neutral conditions) compared to other aspartic proteinases (acid pH 2-4).
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PMID:Inhibition of porcine pepsin by two substrate analogues containing statine. The effect of histidine at the P2 subsite on the inhibition of aspartic proteinases. 312 96

A structure-conformation-activity investigation of several angiotensinogen (ANG) based inhibitors of human renin modified by either Phe-Phe, Sta, Leu psi[CH2NH]Val, or Leu psi[CH(OH)CH2]Val at the P1-P1' clevage site and P5 Trp(Nin-For) (Ftr) was performed. Specifically, Ac-Ftr-Pro-Phe-His-Phe-Phe-Val-Ftr-NH2 (1) provided a potent (KI = 2.7 X 10(-8) M) P1-P1' Phe-Phe substituted renin inhibitor to initiate these studies. Substitution of the P1-P1' Phe-Phe in compound 1 by Sta effected a 1,000-fold increase in biological potency for the resultant octapeptide Ac-Ftr-Pro-Phe-His-Sta-Val-Ftr-NH2 (10; KI = 6.7 X 10(-11) M). Kinetic analysis of compound 10 showed it to be a competitive inhibitor of human renin catalyzed proteolysis of human ANG. Chemical modifications of the compounds 1 and 10 were evaluated on the basis of comparative human plasma renin inhibitory activities (IC50 values) in vitro. Carboxy-terminal truncation studies on compound 10 showed that the P2' Val and P3' Ftr residues could both be eliminated without significant loss (ca. 10-fold) in renin inhibitory activity as exemplified by the pentapeptide Ac-Ftr-Pro-Phe-His-Sta-NH2 (12; IC50 = 3.8 X 10(-9) M). In addition, the corresponding P1-P1' Leu psi[CH(OH)CH2]Val and Leu psi[CH2NH]Val derivatives of compound 12 were potent renin inhibitors: Ac-Ftr-Pro-Phe-His-Leu psi[CH(OH)CH2]Val-NH2 (13; IC50 = 3.1 X 10(-10) M) and Ac-Ftr-Pro-Phe-His-Leu psi[CH2NH]Val-NH2 (14; IC50 = 2.1 X 10(-8) M). The structure-conformation-activity properties of the N-terminal Ftr substitution of these human renin inhibitors was examined by (1) comparative analysis of several analogues of 1 and Ac-Ftr-Pro-Phe-His-Sta-Ile-NH2 (17; IC50 = 1.0 X 10(-10) M) having P5 site modifications by Trp, His, D-Ftr, and D-His, (2) deletion of the N-terminal Ftr residue from compounds 12 and 17, to provide Ac-Pro-Phe-His-Sta-Ile-NH2 (16; IC50 = 3.1 X 10(-8) M) and Ac-Pro-Phe-His-Sta-NH2 (15; IC50 = 5.6 X 10(-6) M), and (3) computer modeling and dynamics studies of compounds 1 and 17 bound to CKH-RENIN, a simulated human renin model, which were focused on identifying potential intermolecular interactions of their common P5-P2 sequence, Ac-Ftr-Pro-Phe-His, at the enzyme active site.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Design, structure-activity, and molecular modeling studies of potent renin inhibitory peptides having N-terminal Nin-For-Trp (Ftr): angiotensinogen congeners modified by P1-P1' Phe-Phe, Sta, Leu psi[CH(OH)CH2]Val or leu psi[CH2NH]Val substitutions. 327 77

The conformational behaviour of pepstatin (Iva-Val-Val-Sta-Ala-Sta) and of two derived renin inhibitors, Boc-Phe-Nle-Sta-Ala-Sta-OMe, 1, and Boc-Phe-Nle-X-Ala-Sta-OMe, 2 (X = -NH-CH(iPr)-CHOH-CH2-CO-) was assessed in DMSO-d6 at various temperatures and in deuteriopyridine at -35 degrees. Complete assignment of almost all proton signals was achieved by 2D COSY, 2D NOESY and selective NOE experiments. The three compounds show similar extended conformations in both solvents, with the hydrophobic lateral chains extending away from the peptide backbone. In the case of pepstatin the solvated conformation is closely related to the structure found in the crystal of the pepstatin-Rhizopus chinensis complex. Strong NOE effects and precise determination of vicinal coupling constants show the lack of large structural differences between 1 and 2 at the level of the internal Sta or X residues, which are assumed to interact with the aspartyl residues of the renin active-site. This suggests that the 100-fold lower inhibitory potency of 2 is mainly due to unfavorable close contacts of the beta-branched residue X with constituent amino acids of the enzyme.
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PMID:Conformational analysis of pepstatin and related renin inhibitors by 400 MHz 1H n.m.r. spectroscopy. 331 53

The in vitro binding of [3H]SR42128 (Iva-Phe-Nle-Sta-Ala-Sta-Arg), a potent inhibitor of human renin activity, to purified human renin and a number of other aspartic proteases was examined. SR42128 was found to be a competitive inhibitor of human renin, with a Ki of 0.35 nM at pH 5.7 and 2.0 nM at pH 7.4; it was thus more effective at pH 5.7 than at pH 7.4. Scatchard analysis of the interaction binding of [3H]SR42128 to human renin indicated that binding was reversible and saturable at both pH 5.7 and pH 7.4. There was a single class of binding sites, and the KD was 0.9 nM at pH 5.7 and 1 nM at pH 7.4. The association rate was 10 times more rapid at pH 5.7 than at pH 7.4, but there was no difference between the rates of dissociation of the enzyme-inhibitor complex at the two pHs. The effect of pH on the binding of [3H]SR42128 to human renin, cathepsin D, pepsin, and gastricsin was also examined over the pH range 3-8. All the aspartic proteases had a high affinity for the inhibitor at low pH. However, at pH 7.4, [3H]SR42128 was bound only to human renin and to none of the other aspartic proteases. Competitive binding studies with [3H]SR42128 and a number of other inhibitors on human renin or cathepsin D were used to examine the relationships between structure and activity in these systems.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A potent radiolabeled human renin inhibitor, [3H]SR42128: enzymatic, kinetic, and binding studies to renin and other aspartic proteases. 332 2

Pepstatin analogues corresponding to the general formula A-X-Y-Sta-Ala-Sta-R were synthesized in solution phase. Various changes in the nature of the A, X, and Y groups were made to improve the inhibitory potency against human plasma renin activity. The results were interpreted by use of the active-site model based on the sequence of human angiotensinogen. The tert-butyloxycarbonyl group and the isovaleryl group were found to be the most effective acyl groups (A). The analogues having a Phe residue in place of Val1 (X) and His or amino acid with an aliphatic side chain such as norleucine or norvaline in the Y position showed the highest inhibition of human plasma renin activity with IC50 values of about 10(-8)M. Esterification or amidification of the carboxyl group of the C-terminal statine did not change the inhibitory potency. The selectivity for rat, dog, pig, and monkey plasma renin of the most interesting compounds was studied.
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PMID:Pepstatin analogues as novel renin inhibitors. 354 58

Analogues of the renin octapeptide substrate were synthesized in which replacement of the scissile dipeptide with (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid (statine, Sta) transformed the substrate sequence into potent, transition-state analogue, competitive inhibitors of renin. Synthesis and incorporation of the cyclohexylalanyl analogue of Sta, (3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA), gave the most potent inhibitors of renin yet reported, including N-isovaleryl-L-histidyl-L-prolyl-L-phenylalanyl-L-histidyl-ACHPA-L -leucyl-L- phenylalanyl amide [Iva-His-Pro-Phe-His-ACHPA-Leu-Phe-NH2,3], with renin inhibitions of Ki = 1.6 X 10(-10) M (human kidney renin), IC50 = 1.7 X 10(-10)M (human plasma renin), IC50 = 1.9 X 10(-9)M (dog plasma renin), and IC50 = 2.1 X 10(-8) M (rat plasma renin). This inhibitor 3, containing ACHPA, was 55-76 times more potent vs. human renin than the comparable Sta-containing inhibitor 1 and 17 times more potent vs. dog renin than 1. Inhibitor 3 lowered blood pressure in sodium-deficient dogs, with in vivo potency 19 times that shown by 1, in close agreement with the relative in vitro potencies. Structure-activity results are presented that show the minimal N-terminus for these inhibitors. An ACHPA-containing pentapeptide, N-[(ethyloxy)carbonyl]-L-phenylalanyl-L- histidyl-ACHPA-L-leucyl-L-phenylalanyl amide [Etoc-Phe-His-ACHPA-Leu-Phe-NH2,8], retained subnanomolar inhibitory potency. Molecular modelling studies are described that suggested the design of ACHPA.
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PMID:Renin inhibitors. Syntheses of subnanomolar, competitive, transition-state analogue inhibitors containing a novel analogue of statine. 390 31

The interaction between mouse submaxillary gland renin and a statine-containing, iodinated substrate analog inhibitor was studied. The compound, 1 (Boc-His-Pro-Phe-(4-iodo)-Phe-Sta-Leu-Phe-NH2, Sta = (3S,4S)-4-amino-3-hydroxy-6-methyl-heptanoic acid), a statine-containing analog of the renin substrate octapeptide, was a competitive inhibitor of cleavage of synthetic tetradecapeptide renin substrate by mouse submaxillary gland renin, with a Ki of 6.2 x 10(-10) M (pH 7.2, 37 degrees C). Titration of the partial quenching of the tryptophan fluorescence of the enzyme by 1 revealed tight binding with a dissociation constant less than 3 nM and a binding stoichiometry of one mole 1 per mole enzyme. The time course of tight binding of 1 to mouse renin appeared to be fast, with kON greater than or equal to 1.3 x 10(6) s-1 M-1. The UV difference spectrum generated upon binding of 1 to mouse renin had two prominent features: a strong, broad band that had a minimum at 242 nm with delta epsilon (242) = -19,500 cm-1 M-1, and a triplet of enhanced bands centered at 286 nm with delta epsilon (286) about +1100 cm-1 M-1. The strong, broad, negative band was similar to the difference between the UV absorbance of 1 in methanol and in 0.1 M citrate phosphate pH 7.2. A structure-activity correlation for analogs of 1 showed some moieties of 1 that are important for potent inhibition of mouse renin. The inhibition data for these compounds versus human kidney renin suggested that the solution of the crystal structure of 1 bound to mouse renin will provide useful information for the design of inhibitors of human kidney renin.
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PMID:Interaction of mouse submaxillary gland renin with a statine-containing, subnanomolar, competitive inhibitor. 391 10


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