title: A new strategy for metabolic stabilization of motilin using the C-terminal part of ghrelin.
abstract: 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 ((15)RKESKK(20)) 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.
authors.affiliation: Faculty of Pharmacology I, Asubio Pharma Co, Ltd, 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan. morozumi.naomi.dg@asubio.co.jp
authors.forename: Naomi
authors.initials: N
authors.lastname: Morozumi
authors.forename: Seiji
authors.initials: S
authors.lastname: Sato
authors.forename: Sayaka
authors.initials: S
authors.lastname: Yoshida
authors.forename: Akira
authors.initials: A
authors.lastname: Yamaki
authors.forename: Mayumi
authors.initials: M
authors.lastname: Furuya
authors.forename: Norio
authors.initials: N
authors.lastname: Inomata
authors.forename: Norio
authors.initials: N
authors.lastname: Ohnuma
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Minamitake
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ohsuye
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001711:Biotransformation; D016466:CHO Cells; D006224:Cricetinae; D054439:Ghrelin / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009037:Motilin / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D055550:Protein Stability; D051381:Rats; D017207:Rats, Sprague-Dawley; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists; D018013:Receptors, Neuropeptide / Q000819:agonists; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D054439:Ghrelin; D010446:Peptide Fragments; D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; D011993:Recombinant Fusion Proteins; C050802:motilin receptor; D009037:Motilin