Inhibition of ghrelin action in vitro and in vivo by an RNA-Spiegelmer
- Steffen Helmling*,
- Christian Maasch*,
- Dirk Eulberg*,
- Klaus Buchner*,
- Werner Schröder*,
- Christian Lange*,
- Stefan Vonhoff*,
- Britta Wlotzka*,
- Matthias H. Tschöp†,‡,
- Stefan Rosewicz§,¶, and
- Sven Klussmann*,∥
- *NOXXON Pharma AG, Max Dohrn-Strasse 8-10, 10589 Berlin, Germany; †Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, OH 45226; ‡Department of Pharmacology, German Institute of Human Nutrition, 14558 Potsdam-Rehbruecke, Germany; and §Department of Hepatology, Gastroenterology, Endocrinology, and Metabolism, Humboldt University, Charité, Campus Virchow-Klinikum, 13353 Berlin, Germany
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Edited by Donald F. Steiner, University of Chicago, Chicago, IL, and approved July 20, 2004 (received for review June 11, 2004)
Abstract
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.
Footnotes
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↵ ∥ To whom correspondence should be addressed. E-mail: sklussmann{at}noxxon.net.
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↵ ¶ Deceased May 20, 2004.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: CHO, Chinese hamster ovary; GH, growth hormone; GHS, GH secretagogues; GHS-R1a, GHS receptor 1a.
- Copyright © 2004, The National Academy of Sciences
