Pharmacological characterization of mono-, dual- and tri-peptidic agonists at GIP and GLP-1 receptors
Pharmacological characterization of mono-, dual- and tri-peptidic agonists at GIP and GLP-1 receptors
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GIP 和 GLP-1 受体单肽、双肽和三肽激动剂的药理学特征
DOI：
10.1016/j.bcp.2020.114001
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发表时间：
2020
影响因子：
5.8
通讯作者：
Denise Wootten
中科院分区：
文献类型：
--
作者：
Elita Yuliantie;Sanaz Darbalaei;Antao Dai;Peishen Zhao;Dehua Yang;Patrick M. Sexton;Ming-Wei Wang;Denise Wootten
葡萄糖依赖性胰岛素肽（GIP）是一种肠促胰岛素激素，在脂肪组织、中枢神经系统和骨代谢中具有生理作用。虽然GIP受体（GIPR）的选择性配体尚未在疾病治疗中取得进展，但GIPR的双重和三重激动剂，与胰高血糖素样肽-1 （GLP-1）和胰高血糖素受体联合使用，目前正在临床试验中，预计其对糖尿病患者的疗效将超过GLP-1受体（GLP-1R）激动剂单药治疗。因此，了解这类药物的药理学行为是很重要的。在这项研究中，我们利用重组表达人GIPR或GLP-1R的人胚胎肾293 （HEK293）细胞，探索了信号通路的特异性和GIPR单、双和三激动剂的偏激作用潜力。与GIP（1-42）相比，GIPR单激动剂Pro3GIP和Lys3GIP倾向于ERK1/2磷酸化（pERK1/2），而GLP-1R/GCGR/GIPR的三重激动剂倾向于pERK1/2，相对于β-arrestin2的募集。此外，与GIPR和GLP-1R各自的内源性配体相比，双GIPR/GLP-1R激动剂LY3298176相对于cAMP在GIPR和GLP-1R上的积累都偏向于pERK1/2。这些数据揭示了可能影响临床反应多样性的潜在治疗药物的新药理学特性。
Glucose-dependent insulinotropic peptide (GIP) is an incretin hormone with physiological roles in adipose tissue, the central nervous system and bone metabolism. While selective ligands for GIP receptor (GIPR) have not been advanced for disease treatment, dual and triple agonists of GIPR, in conjunction with that of glucagon-like peptide-1 (GLP-1) and glucagon receptors, are currently in clinical trials, with an expectation of enhanced efficacy beyond that of GLP-1 receptor (GLP-1R) agonist monotherapy for diabetic patients. Consequently, it is important to understand the pharmacological behavior of such drugs. In this study, we have explored signaling pathway specificity and the potential for biased agonism of mono-, dual- and tri-agonists of GIPR using human embryonic kidney 293 (HEK293) cells recombinantly expressing human GIPR or GLP-1R. Compared to GIP(1–42), the GIPR mono-agonists Pro3GIP and Lys3GIP are biased towards ERK1/2 phosphorylation (pERK1/2) relative to cAMP accumulation at GIPR, whereas the triple agonist at GLP-1R/GCGR/GIPR is biased towards pERK1/2 relative to β-arrestin2 recruitment. Moreover, the dual GIPR/GLP-1R agonist, LY3298176, is biased towards pERK1/2 relative to cAMP accumulation at both GIPR and GLP-1R compared to their respective endogenous ligands. These data reveal novel pharmacological properties of potential therapeutic agents that may impact on diversity in clinical responses.