Inhibition of ghrelin action in vitro and in vivo by an RNA-Spiegelmer.
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 IC(50) 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.
Helmling
Steffen
S
NOXXON Pharma AG, Max Dohrn-Strasse 8-10, 10589 Berlin, Germany.
Maasch
Christian
C
Eulberg
Dirk
D
Buchner
Klaus
K
Schröder
Werner
W
Lange
Christian
C
Vonhoff
Stefan
S
Wlotzka
Britta
B
Tschöp
Matthias H
MH
Rosewicz
Stefan
S
Klussmann
Sven
S
D000595:Amino Acid Sequence; D000818:Animals; D054439:Ghrelin; D013006:Growth Hormone / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000378:metabolism / Q000494:pharmacology*; D036361:Peptide Hormones / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
D054439:Ghrelin; D009841:Oligonucleotides; D036361:Peptide Hormones; D013006:Growth Hormone