Department of Regulation Biology, Faculty of Science, Saitama University, Sakura-ku, Saitama 338-8570, Japan.
Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11121-6. doi: 10.1073/pnas.1203561109. Epub 2012 Jun 20.
G protein-coupled receptors (GPCRs) are major drug targets, and their ligands are currently being explored and developed by many pharmaceutical companies and independent researchers. Class A (rhodopsin-like) GPCRs compose a predominant GPCR family; therefore, class A GPCR ligands are in demand. Growth hormone secretagogue receptor (GHS-R) is a class A GPCR that stimulates food intake by binding to its peptide ligand, ghrelin. Therefore, antagonists of GHS-R are expected to exert antiobesity function. In this article, we describe the use of cDNA display to screen for successfully and identify an antagonistic peptide of GHS-R. The antagonistic peptide inhibited the ghrelin-induced increase in intracellular Ca(2+) in vitro (IC(50) = approximately 10 μM) and repressed the contraction of isolated animal stomach in response to ghrelin. Furthermore, peripheral administration of the peptide inhibited the food intake of mice. This work provides new insight into the development of antiobesity drugs and describes a method for the discovery of unique peptide ligands for class A GPCRs.
G 蛋白偶联受体（GPCRs）是主要的药物靶点，目前许多制药公司和独立研究人员都在探索和开发它们的配体。A 类（视紫红质样）GPCR 构成了主要的 GPCR 家族；因此，A 类 GPCR 配体的需求很大。生长激素促分泌素受体（GHS-R）是一种 A 类 GPCR，通过与它的肽配体 ghrelin 结合来刺激食物摄入。因此，GHS-R 的拮抗剂有望发挥抗肥胖作用。在本文中，我们描述了使用 cDNA 展示来筛选和鉴定 GHS-R 的拮抗肽。该拮抗肽在体外抑制 ghrelin 诱导的细胞内 Ca(2+)增加（IC(50)约为 10 μM），并抑制了分离的动物胃对 ghrelin 的收缩反应。此外，该肽的外周给药抑制了小鼠的食物摄入。这项工作为开发抗肥胖药物提供了新的见解，并描述了一种发现 A 类 GPCR 独特肽配体的方法。
