Structural similarity of ghrelin derivatives to peptidyl growth hormone secretagogues.
Ghrelin is a 28-amino acid residue endogenous growth hormone secretagogue. Intensive investigations revealed that the N-terminus tetrapeptide, having octanoyl group at Ser(3), is the minimum active core. In this study, we further explored the structure-function relationships of the active N-terminus portion of ghrelin using a Ca(2+) mobilization assay. The smallest and most potent ghrelin derivative we have found so far is 5-aminopentanoyl-Ser(Octyl)-Phe-Leu-aminoethylamide, showing comparable activity to the natural molecule. In the process of modifying the active core, the ghrelin-derived short analogues emerged structurally close to peptidyl growth hormone secretagogues. The N-terminus modification suggested that Gly(1)-Ser(2) unit works as a spacer, forming adequate distance between N(alpha)-amino group and n-octanoyl group. Replacement of 3rd and 4th amino acid residues to D-isomer suggested that the N-terminal dipeptide contributes to shape the biologically active geometry by effecting conformation of residues in positions 3 and 4.
Matsumoto
M
M
Suntory Institute for Medicinal Research & Development, 2716-1 Kurakake, Akaiwa, Chiyoda-machi, Ohra-gun, Gunma 370-0503, Japan.
Kitajima
Y
Y
Iwanami
T
T
Hayashi
Y
Y
Tanaka
S
S
Minamitake
Y
Y
Hosoda
H
H
Kojima
M
M
Matsuo
H
H
Kangawa
K
K
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D054439:Ghrelin; D005998:Glycine / Q000737:chemistry; D006728:Hormones / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D036361:Peptide Hormones; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D010649:Phenylalanine / Q000737:chemistry; D051381:Rats; D012694:Serine / Q000737:chemistry; D013329:Structure-Activity Relationship
D054439:Ghrelin; D006728:Hormones; D009842:Oligopeptides; D036361:Peptide Hormones; D010455:Peptides; D012694:Serine; D010649:Phenylalanine; D002118:Calcium; D005998:Glycine; C114611:ipamorelin