Synthesis and cardioprotective properties of apelin-12 and its structural analogues

Abstract

The apelin-12 and a number of its analogs, resistant to degradation of proteases, were synthesized by Fmoc- method of SPPS. By-products of synthesis were examined. It was found that serine hydroxyl group was sulfating during the final deprotection of apelin-12 (I) and its analogs. Sulfate moiety of Arg-protecting group transfer into hydroxyl group of Ser. Amount of by-product depends on presence of water in cleavage mixture. Furthermore, the final deprotection of amide analogs of apelin-12 (III, IV) is closed with formation of by-product--4-hydroxybenzylamide, its amount range on 20-8% on reaction mixture accordance HPLC data and also depend on composition of cleavage mixture. Effects of the synthesized peptides on recovery of cardiac function after ischemia were examined in a model of isolated perfused rat heart. Infusions of any of the peptides (I-V) before ischemia resulted in a significant improvement of contractile and pump function recovery compared to the control. Cardioptotective efficacy of the peptides increased in the following rank (I) < (II) = (III) < (IV) = (V).

Structural apelin analogues: mitochondrial ROS inhibition and cardiometabolic protection in myocardial ischaemia reperfusion injury

“…For analogue II (AII), the N-terminal arginine residue was methylated, the methionine residue was changed to l-norleucine and the C-terminal phenylalanine was amidated. They were purified by preparative HPLC and identified by 1 H-NMR spectroscopy and mass spectrometry (Sidorova et al ., 2012 ). The peptide pGuA13 was a commercial product (Phoenix Pharmaceutical, Belmont, CA, USA).…”

Role of the Vasopressin/Apelin Balance and Potential Use of Metabolically Stable Apelin Analogs in Water Metabolism Disorders

“…Numerous technologies, such as PEGylation (44, 45), palmytoylation (46) conjugation to albumin, N-terminal acetylation (33), C-terminal amidation (47), use of unnatural amino acids (15, 33, 42, 48), or main chain modifications (cyclization) (49–51) have now been set up to increase the in vivo plasma half-life of peptides (52). Table 1 summarizes the pharmacological characteristics of the main metabolically stable apelin analogs described in this section.…”

Effects of structural analogues of apelin-12 in acute myocardial infarction in rats

“…Synthesis of this peptide by using a solid phase method and Fmoc technology with a high yield, and increased chemical stability of the modified molecule in comparison with natural A12 have been demonstrated in our recent paper. [30] Therefore, we believe that modification of C-terminal fragments of apelin may be a useful approach to design new therapeutic tools for the treatment of acute coronary syndrome.…”