Fragments of the Galanin Peptide and Their Synthetic Analogues
with the Cardioprotective Effect1
M. E. Palkeevaa, 1, M. V. Sidorovaa, A. S. Molokoedova, M. V. Ovchinnikova, A. A. Az’mukoa,
L. I. Serebryakovaa, O. M. Veselovaa, I. M. Studnevaa, and O. I. Pisarenkoa
aNational Medical Research Center of Cardiology, Ministry of Health Care, Moscow, 121552 Russia
1Abbreviations: Boc, tert-butyloxycarbonyl; DBU, 1,8–diazobicyclo[5.4.0]-undec-7-en; DCM, dichloromethane; DIPEA, N,N-diisopropylethylamine; DMA, N,N-dimethylacetamide; DMF, N,N-dimethylformamide; Fmoc, 9-fluorenylmethyloxycarbonyl; GalR, the galanin receptor; MALDI, the matrix-assisted laser desorption-ionization method; 4-MePip, 4-methylpiperidine; NMM, N-methylmorpholine; NMP, N-methylpyrrolidone; Pbf, 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl; TBTU, N,N,N ',N '-tetramethyl-О-(benzotriazole-1-yl)uronium tetrafluoroborate; TFA, trifluoroacetic acid; Trt, trityl; RZ, the risk zone; MI, myocardiac infarction; CК-МВ, creatine kinase МВ; VS, ventriculus sinister (left ventricle of heart); RDА, the right descending artery; SBP, systolic blood pressure; SPS, the solid phase synthesis; HR, heart rate
1Corresponding author: phone: +7 (495) 414-67-16; e-mail: peptide-cardio@yandex.ru.
Received 18 January, 2019
Abstract—New peptide analogs of galanin corresponding to fragments of the N-terminal sequence were synthesized by an automatic solid-phase method using Fmoc-technology. Incomplete cleavage of the Boc-protection from the Trp indole ring was found during postsynthetic procedures and a method for solving this problem was proposed. Physicochemical properties of a number of natural and synthetic N-terminal fragments of galanin were been studied. A comparative evaluation of cardioprotective action of peptide agonists of the galanin GalR2 receptor was carried out on the model of the regional ischemia and reperfusion of the heart in rats in vivo. The analog that contained the carnosine sequence, H-Trp-Thr-Leu-Asn-Ser-Ala-Gly-Tyr-Leu-Leu-Gly-Pro-βAla-His-OH, was found to most effectively protect the heart from ischemic and reperfusion stress.
Keywords: galanin, N-terminal galanin fragments, the Gal2-receptor, agonists, peptide cardioprotectors, solid-phase peptide synthesis, Trp(Boc) cleavage
DOI: 10.1134/S1068162019040071