Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 166 10 Prague 6, Czech Republic.
J Pharmacol Exp Ther. 2012 Mar;340(3):781-6. doi: 10.1124/jpet.111.185371. Epub 2011 Dec 19.
Ghrelin, the only known peripherally produced and centrally acting peptide that stimulates food intake, is synthesized primarily in the stomach and acts through the growth hormone secretagogue receptor (GHS-R1a). In addition to its orexigenic effect, ghrelin stimulates the release of growth hormone (GH). In this study, we investigated the biological properties of full-length and shortened ghrelin analogs in which octanoylated Ser(3) is replaced with an octanoic acid moiety coupled to diaminopropionic acid (Dpr). Ghrelin analogs stabilized with Dpr(N-octanoyl) in position 3 and noncoded amino acids in position 1 (sarcosine) and/or position 4 (naphthylalanine or cyclohexylalanine) were found to possess affinities similar to those of ghrelin for cell membranes with transfected GHS-R1a. In vivo, the prolonged orexigenic effects of analogs containing Dpr(N-octanoyl)(3) compared with that of ghrelin in adult mice and a similar impact on GH secretion in young mice were found. Full-length [Dpr(N-octanoyl)(3)]ghrelin and its analogs with a noncoded amino acid in position 1 and/or 4 showed significantly prolonged stability in blood plasma compared with that of ghrelin. Ghrelin analogs with a prolonged orexigenic effect are potential treatments for GH deficiency or cachexia that accompanies chronic diseases. Desoctanoylated ghrelin analogs and N-terminal penta- and octapeptides of ghrelin did not show any biological activity.
胃饥饿素是唯一已知的外周产生和中枢作用的肽类物质，可刺激摄食，主要在胃中合成，并通过生长激素促分泌素受体（GHS-R1a）发挥作用。除了其促进食欲的作用外，胃饥饿素还刺激生长激素（GH）的释放。在这项研究中，我们研究了全长和缩短的胃饥饿素类似物的生物学特性，其中 Ser(3)的辛酰化被偶联到二氨基丙酸（Dpr）的辛酸部分取代。在第 3 位稳定的 Dpr(N-辛酰基)和第 1 位（肌氨酸）和/或第 4 位（萘基丙氨酸或环己基丙氨酸）非编码氨基酸的胃饥饿素类似物被发现对转染 GHS-R1a 的细胞膜具有与胃饥饿素相似的亲和力。在体内，与胃饥饿素相比，含有 Dpr(N-辛酰基)(3)的类似物在成年小鼠中具有延长的食欲作用，并且对年轻小鼠的 GH 分泌具有相似的影响。与胃饥饿素相比，全长[Dpr(N-辛酰基)(3)]胃饥饿素及其在第 1 位和/或第 4 位含有非编码氨基酸的类似物在血浆中的稳定性显著延长。具有延长食欲作用的胃饥饿素类似物可能是治疗 GH 缺乏症或伴有慢性疾病的恶病质的潜在方法。去辛酰化的胃饥饿素类似物和胃饥饿素的 N-末端五肽和八肽没有显示出任何生物活性。
