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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Inhibition of ghrelin action in vitro and in vivo by an RNA-Spiegelmer.
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Inhibition of ghrelin action in vitro and in vivo by an RNA-Spiegelmer.

机译:RNA-Spiegelmer在体内外抑制生长激素释放肽的作用。

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摘要

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.
机译:利用体外选择技术,我们已经生成了生物稳定的基于RNA的化合物,即所谓的Spiegelmers,它们特异性结合正辛酰基生长素释放肽,后者是最近发现的1a型生长激素促分泌素(GHS)受体的内源性配体。 Ghrelin是生长激素释放,食物摄入和肥胖的有效刺激剂。我们证明我们的先导化合物,l-NOX-B11,以低纳摩尔亲和力结合生长素释放肽,并抑制生长素释放肽介导的GHS受体在细胞培养中的IC(50)为5 nM。 1-NOX-B11对生长素释放肽的生物活性,正辛酰化形式具有高度特异性。像GHS受体一样,它不识别无活性的未修饰肽,仅需要N末端的五个氨基酸进行相互作用。 i.v.施用聚乙二醇修饰的1-NOX-B11可有效抑制生长素释放肽诱导的大鼠生长激素释放。这些结果表明,循环中的生物活性生长素释放肽的中和导致中枢神经系统中生长素释放肽的分泌作用的抑制。

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