Kinin B1 receptor antagonists with multi-enzymatic resistance properties

2002 ◽  
Vol 80 (4) ◽  
pp. 287-292 ◽  
Author(s):  
Witold Neugebauer ◽  
Paul A Blais ◽  
Stephanie Hallé ◽  
Catherine Filteau ◽  
Domenico Regoli ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Human Platelets ◽  
Converting Enzyme ◽  
Receptor Antagonists ◽  
Rabbit Lung ◽  
Duration Of Action ◽  
Prolonged Duration ◽  
Bradykinin Antagonists

The kinin B1 receptor has been implicated in a variety of pathological states; therefore, potent, selective, and specific antagonists with prolonged duration of action in vivo are needed. Using R-715 (AcLys[D-β-Nal7,Ile8] desArg9BK) as a template, new peptides containing α-MePhe in position 5, Oic in position 2, and AcOrn instead of AcLys at the N-terminal were prepared and tested for their antagonist potency, their selectivity, and their specificity for the kinin B1 receptor. In vitro metabolic stabilities toward aminopeptidase M (from human plasma), aminopeptidase P (from human platelets), and angiotensin-converting enzyme (purified from rabbit lung) were also investigated. The results of this study indicate that the three modifications applied separately are as well tolerated as they are when present conjointly in the template R-715. Indeed, pA2 values of R-715 (ranging from 8.40 to 8.5) do not differ significantly from the analogues R-954 and R-955 (both ranging from 8.4 to 8.6) when measured at kinin B1 receptors from rabbit aortas and human umbilical veins. Moreover, the chemical modifications utilized in the peptides R-954 and R-955 have provided resistance against aminopeptidases M and P, as well as the angiotensin-converting enzyme, unlike the early (e.g., Lys[Leu8]desArg9BK) and more recent (e.g., R-715, B-9858) generations of B1 receptor antagonists. Ongoing in vivo assays will validate the assumption that the analogues R-954 and R-955 have a prolonged duration of action.Key words: bradykinin, antagonists, B1 receptors, peptidases, metabolism.

Further pharmacological evaluation of a novel synthetic peptide bradykinin B2 receptor agonist

2013 ◽  
Vol 394 (3) ◽  
pp. 353-360 ◽  
Author(s):  
Martin Savard ◽  
Julie Labonté ◽  
Céléna Dubuc ◽  
Witold Neugebauer ◽  
Pedro D’Orléans-Juste ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Synthetic Peptide ◽  
Receptor Agonist ◽  
Rabbit Lung ◽  
Hypotensive Action ◽  
Duration Of Action ◽  
Selective Agonist ◽  
Comparable Magnitude

Abstract We recently identified a novel human B2 receptor (B2R) agonist [Hyp3,Thi5,NChg7,Thi8]-bradykinin (NG291) with greater in vitro and in vivo potency and duration of action than natural bradykinin (BK). Here, we further examined its stability and selectivity toward B2R. The hypotensive, antithrombotic, and profibrinolytic functions of NG291 relative to BK and its analogue ([Hyp3,Thi5,(4-Me)Tyr8(ΨCH2NH)Arg9]-BK) (RMP-7) were also tested. Contraction assays using isolated mouse stomachs (containing kinin B1R, B2R, and kininase I- and II-like activities) showed that NG291 is a more potent contractant than BK and is inhibited by HOE-140 (B2R antagonist) but unaffected by R954 (B1R antagonist), whereas both decreased the potency of BK. In stomach tissues from B2R knockout mice, BK maintained its activity via B1R, whereas NG291 had no contractile effect, indicating that it was selective for B2R. Unlike BK, NG291 was not degraded by rabbit lung ACE. Comparing intravenously administered BK and NG291 revealed that NG291 exhibited more potent and prolonged hypotensive action and greater antithrombotic and profibrinolytic activities. These effects were of comparable magnitude to RMP-7 and were absent in B2R knockout mice. We concluded that NG291 is a novel biostable B2R-selective agonist that may prove suitable for investigating the (pre)clinical cardioprotective efficacy of B2R activation.

scholarly journals Novel activity of angiotensin-converting enzyme. Hydrolysis of cholecystokinin and gastrin analogues with release of the amidated C-terminal dipeptide

1989 ◽  
Vol 262 (1) ◽  
pp. 125-130 ◽  
Author(s):  
P Dubreuil ◽  
P Fulcrand ◽  
M Rodriguez ◽  
H Fulcrand ◽  
J Laur ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Chloride Ion ◽  
Peptide Bond ◽  
Major Product ◽  
Enzyme Hydrolysis ◽  
Ion Concentration ◽  
Converting Enzyme ◽  
Rabbit Lung ◽  
Hydrolysis Of

ACE (angiotensin-converting enzyme; peptidyl dipeptidase A; EC 3.4.15.1), cleaves C-terminal dipeptides from active peptides containing a free C-terminus. We investigated the hydrolysis of cholecystokinin-8 [CCK-8; Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2] and of various gastrin analogues by purified rabbit lung ACE. Although these peptides are amidated at their C-terminal end, they were metabolized by ACE to several peptide fragments. These fragments were analysed by h.p.l.c., isolated and identified by comparison with synthetic fragments, and by amino acid analysis. The initial and major site of hydrolysis was the penultimate peptide bond, which generated a major product, the C-terminal amidated dipeptide Asp-Phe-NH2. As a secondary cleavage, ACE subsequently released di- or tri-peptides from the C-terminal end of the remaining N-terminal fragments. The cleavage of CCK-8 and gastrin analogues was inhibited by ACE inhibitors (Captopril and EDTA), but not by other enzyme inhibitors (phosphoramidon, thiorphan, bestatin etc.). Hydrolysis of [Leu15]gastrin-(14-17)-peptide [Boc (t-butoxycarbonyl)-Trp-Leu-Asp-Phe-NH2] in the presence of ACE was found to be dependent on the chloride-ion concentration. Km values for the hydrolysis of CCK-8, [Leu15]gastrin-(11-17)-peptide and Boc-[Leu15]gastrin-(14-17)-peptide at an NaCl concentration of 300 mM were respectively 115, 420 and 3280 microM, and the catalytic constants were about 33, 115 and 885 min-1. The kcat/Km for the reactions at 37 degrees C was approx. 0.28 microM-1.min-1, which is approx. 35 times less than that reported for the cleavage of angiotensin I. These results suggest that ACE might be involved in the metabolism in vivo of CCK and gastrin short fragments.

Interaction of mAb to angiotensin-converting enzyme (ACE) with antigen in vitro and in vivo: antibody targeting to the lung induces ACE antigenic modulation

1994 ◽  
Vol 6 (8) ◽  
pp. 1153-1160 ◽  
Author(s):  
Sergei Danilov ◽  
Elena Atochina ◽  
Holger Hiemisch ◽  
Tatiana Churak-ova ◽  
Aygul Moldobayeva ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Converting Enzyme ◽  
Antigenic Modulation ◽  
Antibody Targeting

DOCKING STUDY OF NOVEL N-SUBSTITUTED 2,5-BIS[(7-CHLOROQUINOLIN-4-YL)AMINO]PENTANOIC DERIVATIVES AS SELECTIVE HIGH-BINDER WITH ANGIOTENSIN CONVERTING ENZYME 2

INDIAN DRUGS ◽  
2020 ◽  
Vol 57 (08) ◽  
pp. 16-24
Author(s):  
Mohammed Oday Ezzat ◽  
Basma M. Abd Razik ◽  
Kutayba F. Dawood
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Active Site ◽  
Docking Study ◽  
World Health ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Pharmaceutical Properties ◽  
Novel Coronavirus

The prevalence of a novel coronavirus (2019-nCoV) in the last few months represents a serious threat as a world health emergency concern. Angiotensin-converting enzyme 2 (ACE2) is the host cellular receptor for the respiratory syndrome of coronavirus epidemic in 2019 (2019-nCoV). In this work, the active site of ACE2 is successfully located by Sitmap prediction tool and validated by different marketed drugs. To design and discover new medical countermeasure drugs, we evaluate a total of 184 molecules of 7-chloro-N-methylquinolin-4-amine derivatives for binding affinity inside the crystal structure of ACE2 located active site. A novel series of N-substituted 2,5-bis[(7-chloroquinolin-4-yl)amino]pentanoic acid derivatives is generated and evaluated for a prospect as a lead compound for (2019-nCoV) medication with a docking score range of (-10.60 to -8.99) kcal/mol for the highest twenty derivatives. Moreover, the ADME pharmaceutical properties were evaluated for further proposed experimental evaluation in vitro or in vivo

Angiotensin-converting enzyme determination in plasma during therapy with converting enzyme inhibitor: two methods compared

1991 ◽  
Vol 37 (8) ◽  
pp. 1390-1393 ◽  
Author(s):  
T P Gorski ◽  
D J Campbell
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Spectrophotometric Method ◽  
Enzyme Inhibitor ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Fluorometric Method ◽  
Converting Enzyme Inhibitor ◽  
Ace Activity

Abstract For normal and above-normal concentrations of angiotensin-converting enzyme (ACE; EC 3.4.15.1) activity in plasma, results of a manual fluorometric method [with hippuryl-histidyl-leucine (HHL), 5 mmol/L, as substrate] correlated well with those of an automated spectrophotometric method [with 3-(2-furylacryloyl)-L-phenylalanyl-glycyl-glycine (FAPGG), 2 mmol/L, as substrate]. However, for patients receiving converting enzyme inhibitor (CEI) therapy, the spectrophotometric method showed much greater suppression of plasma ACE activity than did the fluorometric method. To determine which of the two methods provided a more reliable indication of ACE inhibition in vivo, we measured plasma ACE, angiotensin I (ANG I), and angiotensin II (ANG II) in patients receiving the CEI perindopril. During perindopril therapy, changes in the ratio of ANG II:ANG I, an index of ACE activity in vivo, showed a close agreement with changes in plasma ACE activity measured with FAPGG as substrate, but not with HHL as substrate. We conclude that measurement of ACE activity in vitro with FAPGG as substrate provides a reliable measure of changes in conversion of ANG I to ANG II in vivo during CEI therapy.

Angiotensin Converting Enzyme Activity in Human Serum: Relationship to Enzyme Inhibitor In Vivo and In Vitro

1982 ◽  
Vol 127 (2) ◽  
pp. 396-396
Author(s):  
B.N. Swanson ◽  
M. Hichens ◽  
P. Mojaverian ◽  
R.K. Ferguson ◽  
P.H. Vlasses ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Angiotensin Converting Enzyme ◽  
Human Serum ◽  
Enzyme Inhibitor ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme Activity

Endothelial cells internalize monoclonal antibody to angiotensin-converting enzyme

1996 ◽  
Vol 270 (5) ◽  
pp. L704-L713 ◽  
Author(s):  
V. R. Muzykantov ◽  
E. N. Atochina ◽  
A. Kuo ◽  
E. S. Barnathan ◽  
K. Notarfrancesco ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Endothelial Cells ◽  
Angiotensin Converting Enzyme ◽  
Umbilical Vein ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Affinity Constant ◽  
Converting Enzyme

We investigated the fate of MAb 9B9, a monoclonal antibody to angiotensin-converting enzyme (ACE), which binds to endothelium both in vitro and in vivo. Using cultured human umbilical vein endothelial cells (HUVEC) and isolated perfused rat lungs (IPL), we demonstrated specific and saturable binding of 125I-labeled MAb 9B9 at 4 degrees C [affinity constant (Kd) = 20-50 nM, maximal number of binding sites (Bmax) = 1.5-3.0 x 10(5) sites/cell]. When 125I-MAb 9B9 was bound to HUVEC at 37 degrees C, only 40% of cell-associated radioactivity was acid elutable, suggesting antibody internalization. This was confirmed by finding that 1) the amount of MAb 9B9 uptake at 37 degrees C was higher than at 4 degrees C both in HUVEC and IPL; 2) binding of 125I-labeled streptavidin with HUVEC and IPL pretreated with biotinylated MAb 9B9 (b-MAb 9B9) was diminished in a temperature- and time-dependent fashion at 37 degrees C; and 3) b-MAb 9B9 bound to HUVEC at 37 degrees C was found intracellularly by ultrastructural analysis using streptavidin gold. Intracellular 125I-MAb 9B9 was found in microsomal fractions of lung homogenate from IPL and after intravenous (iv) injections in rats. Degradation of internalized MAb 9B9 was minimal, since > 90% of cell-associated 125I label remained precipitable by trichloracetic acid in HUVEC, IPL, and in vivo. Autoradiography of sodium dodecyl sulfate-polyacrylamide gel electrophoresis of lung homogenates made as late as several days after iv injections of 125I-MAb 9B9 in rats demonstrated a predominant band above 140 kDa. These data indicate that endothelial cells either in vitro or in vivo internalize the ACE ligand MAb 9B9 without significant intracellular degradation. Therefore MAb 9B9 may be useful for selective intracellular delivery of drugs to the pulmonary vascular endothelium after systemic administration.

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