Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Selective, as well as mixed, inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE), are of major clinical interest in the treatment of hypertension and cardiac failure. New thiol inhibitors, corresponding to the general formula HS-CH(R1)-CH2-CH(R2)-CONH-CH(R3)-COOH, were designed in order to explore the putative S1 subsite of the active site of NEP. The inhibitors were also tested on ACE and the most representative on thermolysin (TLN) for comparison. The relatively low inhibitory potencies exhibited by these compounds (IC50S in the 10(-7) M range for NEP and in the 10(-6) M range for ACE) as compared to that of thiorphan (IC50S 2.10 x 10(-9) M on NEP and 1.40 x 10(-7) M on ACE) clearly indicate the absence of the expected energetically favorable interactions with the active site of both peptidases. A 100-fold loss of potency for these inhibitors was also observed for thermolysin as compared to thiorphan. Using the mutated Glu102-NEP, it was possible to demonstrate that the inhibitors do not fit the S1 subsite of NEP but interact with the S'1 and S'2 subsites through binding of their R1 and R2 residues and that the C-terminal amino acid is located outside the active site. These results seem to indicate that these thiol inhibitors are not well adapted for optimal recognition of the S1 subsite of NEP, and probably ACE, and that other zinc-chelating moieties such as carboxylate or phosphonate groups may be preferred for this purpose.
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PMID:New thiol inhibitors of neutral endopeptidase EC 3.4.24.11: synthesis and enzyme active-site recognition. 802 26

Arterial tone and water-electrolyte homeostasis are regulated by several peptides, including angiotensin II (AII), bradykinin (BK), atrial natriuretic peptide (ANP) and endothelins (ETs). Changing the concentrations of these peptides in the plasma, tissue, or urine by decreasing the levels of angiotensin II and endothelins and increasing BK and ANP concentrations, is one way of modulating the hemodynamic load. The metabolism of these peptides in essentially controlled by three enzymes, angiotensin-converting enzyme (ACE), neutral endopeptidase (NEP), and endothelin converting enzyme (ECE), which all belong to the group of zinc metallopeptidases. Inhibition of these peptidases by a single compound (a dual inhibitor) that inhibits at once angiotensin II formation and BK and ANP inactivation, causes vasodilatation with reduction in blood pressure with reduction in blood pressure and increases natriuresis. The design of these inhibitors has often be relied on structure-activity studies, based on active-site models derived from structural data on thermolysin (TLN). The results of a large number of pharmacological experiments and those issued from some clinical studies using selective or mixed inhibitors show that in spontaneously hypertensive rats, dual ACE/NEP inhibitors such as S21,402 produce dose-related decreases (-15 to -40 mmHg) in mean arterial pressure and reductions in left ventricular hypertrophy and cardiac size. These compounds produce also an increase in urinary levels of BK, ANP and cGMP associated with enhanced urine output and sodium excretion. Moreover inhibition of NEP appears to improve the cardio- and reno-protective effects resulting from ACE inhibition and could also reduce hypertrophy of vascular walls. Inhibition of ECE seems to result in a weak reduction in blood pressure, an effect which could be emphasized by using dual ECE/ACE or ECE/NEP inhibitors. According to these results mixed dual inhibitors could be of great interest for the treatment of severe hypertension and chronic heart failure. Potent triple inhibitors blocking ACE, NEP and ECE could also be developed.
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PMID:Cell surface metallopeptidases involved in blood pressure regulation: structure, inhibition and clinical perspectives. 976 15

The angiotensin-converting enzyme (ACE) exhibits critical functions in the conversion of angiotensin I to angiotensin II and the degradation of bradykinin and other vasoactive peptides. As a result, the ACE inhibition has become a promising approach in the treatment of hypertension, heart failure, and diabetic nephropathy. Extending our recent molecular dynamics simulation of the testis ACE in complex with a bona fide substrate molecule, hippuryl-histidyl-leucine, we presented here a detailed investigation of the hydrolytic process and possible influences of the chloride ion on the reaction using a combined quantum mechanical and molecule mechanical method. Similar to carboxypeptidase A and thermolysin, the promoted water mechanism is established for the catalysis of ACE. The E384 residue was found to have the dual function of a general base for activating the water nucleophile and a general acid for facilitating the cleavage of amide C-N bond. Consistent with experimental observations, the chloride ion at the second binding position is found to accelerate the reaction rate presumably due to the long-range electrostatic interactions but has little influence on the overall substrate binding characteristics.
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PMID:Catalytic mechanism of angiotensin-converting enzyme and effects of the chloride ion. 2367 66