Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

Five new cathepsin D inhibitors were synthesized and tested as inhibitors of bovine cathepsin D. The compounds were derived by replacing a Phe-Phe dipeptidyl unit of a good cathepsin D substrate, Boc-Phe-Leu-Ala-Phe-Phe-Val-Leu-OR, with statine [3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, Sta) or with Sta-Phe. The best inhibitor, Boc-Phe-Leu-Ala-(S,S)-Sta-Val-Leu-OMe, inhibited cathepsin D with a Ki value of 1.1 nM. In general, the more effective inhibitors were consistent with the proposal that statine functions as a replacement for a dipeptidyl unit. Thirty-five known pepstatin analogues also were evaluated as cathepsin D inhibitors. Substituents in the P4 and P3' positions are important for maximal inhibition of this aspartic proteinase, and the P4 substituent appears more important for inhibition of cathepsin D than for inhibition of other aspartic proteinases.
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PMID:Inhibition of cathepsin D by substrate analogues containing statine and by analogues of pepstatin. 378 11

Inhibition of renin was induced in conscious marmosets with CGP 29 287, Z-Arg-Arg-Pro-Phe-His-Sta-Ile-His-Lys (Boc)-OMe, a renin inhibitor with a prolonged duration of action. In vitro, CGP 29 287 is a potent inhibitor of primate plasma renin (inhibitory concentration, 50%: human = 1 X 10(-9) M; marmoset = 5 X 10(-9) M) and less potent against dog (2 X 10(-7) M) or rat (3 X 10(-5) M) plasma renin. CGP 29 287 is a weak inhibitor of other aspartic proteases such as porcine pepsin or bovine cathepsin D (inhibitory concentration, 50% = 4 X 10(-5) M). In furosemide-treated marmosets, CGP 29 287 lowered blood pressure and inhibited plasma renin activity during intravenous infusion and after intravenous bolus injection. The duration of action after intravenous injection was dose dependent and ranged from 1 hour after 0.1 mg/kg to more than 3 hours after 10 mg/kg. High doses of CGP 29 287 (100 mg/kg) were active after oral administration. In all experiments a close relation between inhibition of plasma renin activity and reduction of blood pressure was found. A maximum hypotensive response to CGP 29 287 was associated with complete inhibition of plasma renin activity, and the recovery of blood pressure was accompanied by recovery of plasma renin activity. The hypotensive effects of CGP 29 287 were smaller in untreated than in furosemide-treated marmosets. CGP 29 287 had no influence on blood pressure in marmosets after bilateral nephrectomy or after pretreatment with a converting enzyme inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of a specific and long-acting renin inhibitor in the marmoset. 392 88