Conformational analysis of yvae peptide derivatives
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CONFORMATIONAL ANALYSIS OF YVAE PEPTIDE DERIVATIVES
V. V. Pak,1* D. Y. Kwon,1 L. M. Yun,1 A. Yili,2 H. A. Aisa,2 and Kh. M. Shakhidoyatov3
UDC 547.964
Active conformations of YVAE peptide derivatives that were competitive inhibitors of 3-hydroxy3-methylglutaryl–coenzyme A reductase (HMG–CoA reductase) were determined. A type I E-turn in N-terminuses of the studied peptides was shown to be present. The steric positioning of active conformations of peptides and statins revealed the structure–function similarity between these compounds. The results agreed with the observed increase of inhibitor activity in the studied series of peptides. Keywords: peptide, inhibitor, HMG–CoA reductase, circular dichroism, statins. 3-Hydroxy-3-methylglutaryl–coenzyme A reductase (HMG–CoA reductase) is a key enzyme in the biosynthesis of cholesterol [1]. Many researchers are studying the mechanism of action of HMG–CoA reductase inhibitors and their effect on the blood cholesterol level in order to create more effective and safe biologically active compounds. Application of cholesterol biosynthesis inhibitors is important because of the reduced risk of hypercholesterolemia that, as is known, is the main risk factor of various cardiovascular diseases [2, 3]. Some of the most widely used drugs for treating cardiovascular diseases are statins. Statins are competitive inhibitors of HMG–CoA reductase that are active in nanomolar amounts (IC50 = 2–24 nM). Results of controlled clinical trials using statins showed that they exhibit hypolipidemic activity, reduced cardiovascular and overall lethality, and improve the quality of life and prognosis of patients with ischemic heart disease (IHD) and atherosclerosis [2, 3]. Statistical studies that found a lower level of atherosclerosis in populations of Asian countries compared with Europe and the Americas were used in the search for new inhibitors. The analysis showed that this effect was due to a high utilization of soy protein and products based on it [4, 5]. A peptide (IAVPGEVA) that inhibited HMG–CoA reductase was isolated in a previous investigation of soy protein and is given below [6]: Compound
IC50, nÌ
Compound
IC50, nÌ
IAVPGEVA YVAE FGYVAE GFYVAE DFGYVAE
201000 41210 410 270 160
SFGYVAE Compactin Atorvastatin Rozuvastatin
33 24 10 2
Kinetic studies showed that the isolated peptide was a competitive inhibitor of this enzyme. Taking this amino-acid sequence as a basis, we designed another peptide (YVAE) where the side radical of the amino-acid residue E was the recognized part for the HMG binding site in the enzyme active center [7]. In the next step, another series of peptides was designed, among which the FGYVAE peptide was the most active [8]. Kinetic studies also confirmed the competitive inhibition of HMG–CoA reductase by this peptide. Conformational analysis revealed the presence of a type I E-turn at the N-terminus of this peptide [6]. Yet another series in which DFGYVAE (1) and SFGYVAE (2) were the most active competitive inhibitors of HMG–CoA reductase was designed in order
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