Ghrelin is a 28-amino acid residue endogenous growth hormone secretagogue,
Intensive investigations revealed that the N-terminus tetrapeptide, having
octanoyl group at Sers, is the minimum active core. In this study, we furth
er explored the structure-function relationships of the active N-terminus p
ortion of ghrelin using a Ca2+ mobilization assay. The smallest and most po
tent ghrelin derivative we have found so far is 5-aminopentanoyl-Ser(Octyl)
-Phe-Leu-aminoethylamide, showing comparable activity to the natural molecu
le, In the process of modifying the active core, the ghrelin-derived short
analogues emerged structurally close to peptidyl growth hormone secretagogu
es. 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-octan
oyl group. Replacement of 3rd and 4th amino acid residues to D-isomer sugge
sted that the N-terminal dipeptide contributes to shape the biologically ac
tive geometry by effecting conformation of residues in positions 3 and 4. (
C) 2001 Academic Press.