Scientists found that a tiny piece of the hormone ghrelin, when tweaked slightly, works just as well as the full hormone at triggering growth hormone release. This shows that very short, modified peptides can be powerful, which is useful for people looking at ghrelin‑like compounds such as ipamorelin.

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.