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Designing Spiegelmers to antagonise ghrelin
  1. P J Hornby
  1. Correspondence to:
    Dr P J Hornby
    Enterology Biology Team Leader, Johnson & Johnson, Research and Development L L C, UK; phornby{at}prdus.jnj.com

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Use of an anti-ghrelin Spiegelmer could be an innovative new approach to inhibit the biological actions of circulating ghrelin

The article by Kobelt and colleagues1 in this issue of Gut, further explores a novel mechanism to interfere with the action of ghrelin on its receptor, growth hormone secretagogue receptor 1 (GHS-R) (see page 788). Ghrelin is a 28 amino acid peptide localised immunocytochemically in parietal cells of the human stomach2 where it is released and stimulates growth hormone release, food intake, and adiposity. Human plasma has relatively low levels of ghrelin3 although, somewhat counter intuitively, in anorectic patients the fasting level of ghrelin, including the active form (n-octanoyl modification at serine 3), is significantly higher.4 The main impact of this work is that the investigators have demonstrated the efficacy of and dose related inhibition of ghrelin stimulated food intake in rats. They did this by using a biological approach to bind to ghrelin and prevent the interaction of ghrelin with its receptor in vivo. These data support the results of an earlier study whereby the same approach inhibited ghrelin stimulated growth hormone release in vivo.5

Biological, as opposed to small molecule, manipulation of receptors and enzymes has gained acceptance in experimental basic science and clinically. Examples of these types of approaches are monoclonal antibodies, with high specificity and affinity for proteins, and antisense technology to prevent gene expression. Modulation of gene expression has shown promise in clinical trials—for example, antisense treatment to reduce a cellular adhesion molecule has been shown to be effective in inflammatory bowel disease.6 In this article by Kobelt and colleagues,1 the approach taken has been to use a single stranded oligonucleotide “mirror image” (that is, Spiegelmer), to inhibit the effects of exogenous ghrelin. Spiegelmers are …

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