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.
NOXXON Pharma AG, Max Dohrn-Strasse 8-10, 10589 Berlin, Germany.
Steffen
S
Helmling
Christian
C
Maasch
Dirk
D
Eulberg
Klaus
K
Buchner
Werner
W
Schröder
Christian
C
Lange
Stefan
S
Vonhoff
Britta
B
Wlotzka
Matthias H
MH
Tschöp
Stefan
S
Rosewicz
Sven
S
Klussmann
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