In vitro screening of peptides and glycopeptides inhibitors of angiotensin I-converting enzyme
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1
Institute of Neurobiology, Dept.Drug Toxicology, Bulgaria
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2
Bulgarian Academy of Sciences, Institute of Organic Chemistry with Center of Phytochemistry, Bulgaria
Introduction. Angiotensin I-converting enzyme (ACE) is a zinc-containing metalloprotein. It releases dipeptides from the C-terminus of the peptide substrates as angiotensin I and bradykinin leading to the synthesis of angiotensin II and breakdown of bradykinin thus inducing vasoconstriction. ACE inhibitors are among the most powerful drugs for regulation of blood pressure.
In the present communication, the first results of in vitro testing of some peptides and glycopeptides inhibitors of ACE are presented.
Materials and methods. An original method was applied for ACE activity determination. Rabbit serum was used as enzyme source. Serum aliquot was incubated in buffered medium with the ACE substrate analogue Hippuryl-Histidyl-Leucine (HHL). The hippuric acid produced is extracted and quantified relative to an internal standard by High Performance Liquid Chromatography (HPLC). The amount of hippuric acid formed reflects the ACE activity.
Tree different proline peptides derivatives, two tree- and tetra- peptides derivatives and two aminocarbohydrates were tested for their inhibitory potency compared with the well known ACE inhibitors: Lisinopril (pyrrolidine derivative which is not metabolized and excreted unchanged in the urine) and Fosinoprilat (active metabolite of fosinopril, an pyrrolidine derivative).
The IC50 and IC100 values were determined by non-linear regression analysis of enzyme activity/inhibitor concentrations curves using software package GraphPad Prism 5.0.
Results.From the six compounds studied, the highest inhibitory potency possessed Val-Pro-Pro-OH with IC50 around 26 µM, followed by CF3-COOH-Val-Pro-Pro-Pro (IC50 around 0.51 mM), and HCl.Val-Pro-OH (IC50 around 0.9 mM). HCl.Suc-Val-OH, HCl-Glu-Val-OH and Suc-Boc-Val were ineffective up to 1 mM concentration. The inhibitory effect of Lisinopril and Fosinoprilat is much greater than that of Val-Pro-Pro-OH. The enzyme activity is 100% inhibited after 40 nM.
Conclusion. The significant inhibition of ACE activity by some peptides derivatives is a good base for the synthesis of new compounds with greater inhibitory potency.
Keywords:
Angiotensin I-converting enzyme,
ACE inhibitors
Conference:
8th Southeast European Congress on Xenobiotic Metabolism and Toxicity - XEMET 2010, Thessaloniki, Greece, 1 Oct - 5 Oct, 2010.
Presentation Type:
Poster
Topic:
Xenobiotic toxicity
Citation:
Pandova
B,
Todorova
V,
Yakimova
B,
Yanev
S,
Stoineva
I and
Chorbanov
B
(2010). In vitro screening of peptides and glycopeptides inhibitors of angiotensin I-converting enzyme.
Front. Pharmacol.
Conference Abstract:
8th Southeast European Congress on Xenobiotic Metabolism and Toxicity - XEMET 2010.
doi: 10.3389/conf.fphar.2010.60.00171
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Received:
28 Oct 2010;
Published Online:
04 Nov 2010.
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Correspondence:
Dr. Bozhidarka Pandova, Institute of Neurobiology, Dept.Drug Toxicology, Sofia, Bulgaria, stanislav_yanev@yahoo.com