In vitro selection of a peptide antagonist of growth hormone secretagogue receptor using cDNA display
In vitro selection of a peptide antagonist of growth hormone secretagogue receptor using cDNA display
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DOI：
10.1073/pnas.1203561109
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发表时间：
2012-07-10
影响因子：
11.1
通讯作者：
Sakai, Takafumi
中科院分区：
文献类型：
--
作者：
Ueno, Shingo;Yoshida, Sayaka;Sakai, Takafumi
G蛋白偶联受体(GPCRs)是主要的药物靶点，其配体目前正在被许多制药公司和独立研究人员探索和开发。A类(视紫红质样)GPCRs构成了占主导地位的GPCRs家族，因此，对A类GPCRs的需求很大。生长激素促分泌素受体(GHS-R)是一种A类GPCR，通过与其多肽配体Ghrelin结合来刺激食物的摄取。因此，GHS-R拮抗剂有望发挥减肥作用。在本文中，我们描述了利用cDNA展示技术成功地筛选和鉴定GHS-R的拮抗肽。该拮抗肽在体外可抑制Ghrelin引起的细胞内钙离子浓度升高(IC50约为10mU M)，并抑制Ghrelin引起的离体胃收缩。此外，外周给药抑制了小鼠的食物摄入量。这项工作为减肥药物的开发提供了新的见解，并描述了一种发现A类GPCRs的独特多肽配体的方法。
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 Ca2+ in vitro (IC50 = approximately 10 mu M) 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.