Details

Autor(en) / Beteiligte

• Helmling, Steffen
• Maasch, Christian
• Eulberg, Dirk
• Buchner, Klaus
• Schröder, Werner
• Lange, Christian
• Vonhoff, Stefan
• Wlotzka, Britta
• Tschöp, Matthias H.
• Rosewicz, Stefan
• Klussmann, Sven
• Steiner, Donald F.

Titel

Inhibition of Ghrelin Action in vitro and in vivo by an RNA-Spiegelmer

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2004-09, Vol.101 (36), p.13174-13179

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2004

Quelle

MEDLINE

Beschreibungen/Notizen

• Employing in vitro selection techniques, we have generated biostable RNA-based compounds, so-called Spiegelmers, that specifically bind n-octanoyl ghrelin, the recently discovered endogenous ligand for the type 1a growth hormone secretagogue (GHS) receptor. Ghrelin is a potent stimulant of growth hormone release, food intake, and adiposity. We demonstrate that our lead compound, L-NOX-B11, binds ghrelin with low-nanomolar affinity and inhibits ghrelin-mediated GHS-receptor activation in cell culture with an IC50 of 5 nM. L-NOX-B11 is highly specific for the bioactive, n-octanoylated form of ghrelin. Like the GHS receptor, it does not recognize the inactive unmodified peptide and requires only the N-terminal five amino acids for the interaction. The i.v. administration of polyethylene glycol modified L-NOX-B11 efficiently suppresses ghrelin-induced growth hormone release in rats. These results demonstrate that the neutralization of circulating bioactive ghrelin leads to inhibition of ghrelin's secretory effects in the CNS.