A new strategy for metabolic stabilization of motilin using the C-terminal part of ghrelin

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• 作者：Naomi Morozumi^a ; ^{morozumi.naomi.dg@asubio.co.jp} ; Seiji Sato^b ; Sayaka Yoshida^a ; Akira Yamaki^a ; Mayumi Furuya^a ; Norio Inomata^a ; Norio Ohnuma^c ; Yoshiharu Minamitake^c ; Kazuhiro Ohsuye^c ; Kenji Kangawa^d
• 关键词：PK ; pharmacokinetic ; ip ; intra-peritoneal ; iv ; intravenous ; RIA ; radio-immuno assay ; GPR38 ; G protein-coupled receptor 38 ; GHS-R1a ; growth hormone secretagogue receptor 1a ; GH ; growth hormone ; [Ca2+]i ; intracellular calcium concentrations ; T1/2 ; terminal
• 刊名：Peptides
• 出版年：2012
• 期刊代码：59_01969781
• 类别：neu
• 出版时间：February, 2012
• 卷：33
• 期：2
• 页码：279-284
• 文件大小：360 K

摘要

Ghrelin consists of 28 amino acid residues with an octanoyl modification at the third serine residue. Recently we have found that the C-terminal part of ghrelin protects the ester bond of 3-octanoyled serine from plasma esterases and plays the essential role to prolong the plasma half-life and to show its biological activity in vivo. In the present study, we researched whether the C-terminal part of ghrelin has a potential to prolong the plasma half-life of motilin, by comparing the pharmacokinetics of various chimeric peptides of ghrelin and motilin. Motilin is another gastro-intestinal peptide hormone related with ghrelin structurally, binding to the same family of G protein-coupled receptors. Chimeric peptides were designed to be composed of motilin(1-12) fragment, the active core binding to the motilin receptor, GPR38, and C-terminal part of ghrelin. The modification of motilin(1-12) fragment by C-terminal part of ghrelin hardly influenced its agonist activity to GPR38 and almost all these chimeric peptides showed more than two times longer plasma half-lives than motilin in rats. From the relationship between structures of chimeric peptides and their corresponding plasma half-lives, the mid-region of ghrelin rich in basic amino acids (¹⁵RKESKK²⁰) was considered to be the most important in prolonging the plasma half-life of motilin. The deletion of these fragments or replacement of 17th glutamic acid with a neutral amino acid resulted in short plasma half-lives. In conclusion, our data suggested that the C-terminal part of ghrelin has a potential to improve the biokinetics of motilin probably by a metabolic stabilizing effect.