Evaluation of biased agonism mediated by dual agonists of the GLP-1 and glucagon receptors
Evaluation of biased agonism mediated by dual agonists of the GLP-1 and glucagon receptors
复制标题
GLP-1 和胰高血糖素受体双重激动剂介导的偏向激动作用的评估
DOI：
10.1016/j.bcp.2020.114150
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发表时间：
2020-10-01
影响因子：
5.8
通讯作者：
Wootten, Denise
中科院分区：
文献类型：
--
作者：
Darbalaei, Sanaz;Yuliantie, Elita;Wootten, Denise
代谢性疾病如肥胖、糖尿病及其合并症已成为全球范围内最严重的健康问题之一。选择性胰高血糖素样肽-1（GLP-1）受体（GLP-1 R）激动剂是2型糖尿病和肥胖症的主要治疗药物之一。能够在单一药物中调节多个代谢靶点的多药理学方法已成为改善治疗结果的潜在途径。在众多开发中的肽中，靶向GLP-1 R和胰高血糖素受体（GCGR）、葡萄糖依赖性促胰岛素肽受体（GIPR）或所有3种受体的肽作为双肽或三肽激动剂。尽管他们中的许多人进入临床试验，目前的发展一直是基于对这些配体的结合选择性以外的潜在药理学性质的谱的有限理解。在本研究中，我们检查了靶向GLP-1 R和GCGR的激动剂表现出偏倚激动作用的可能性，比较了Gs蛋白近端激活、cAMP蓄积、pERK 1/2和β-抑制蛋白募集的活性。检查了对GLP-1 R与GCGR具有不同相对cAMP产生效价的三种不同双重激动剂“肽15”、MEDI 0382和SAR 425899，以及GLP-1 R、GCGR和GIPR的一种三激动剂。我们证明，所有新的肽相对于受体的同源激动剂中的任一种以及彼此具有不同的偏向激动作用曲线。这是该类药物药理学的一个重要特征，需要与选择性、生物利用度和药代动力学一起考虑，以合理优化新疗法。
Metabolic diseases such as obesity, diabetes, and their comorbidities have converged as one of the most serious health concerns on a global scale. Selective glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists are one of the major therapeutics for type 2 diabetes and obesity. Polypharmacological approaches that enable modulation of multiple metabolic targets in a single drug have emerged as a potential avenue to improve therapeutic outcomes. Among numerous peptides under development are those targeting the GLP-1R and either the glucagon receptor (GCGR), glucose-dependent insulinotropic peptide receptor (GIPR) or all 3 receptors, as dual- or tri- peptide agonists. Despite many of them entering into clinical trials, current development has been based on only a limited understanding of the spectrum of potential pharmacological properties of these ligands beyond binding selectivity. In the present study, we examined the potential for agonists that target both GLP-1R and GCGR to exhibit biased agonism, comparing activity across proximal activation of Gs protein, cAMP accumulation, pERK1/2 and beta-arrestin recruitment. Three distinct dual agonists that have different relative cAMP production potency for GLP-1R versus GCGR, "peptide 15", MEDI0382 and SAR425899, and one triagonist of the GLP-1R, GCGR and GIPR were examined. We demonstrated that all novel peptides have distinct biased agonism profiles relative to either of the cognate agonists of the receptors, and to each other. This is an important feature of the pharmacology of this drug class that needs to be considered alongside selectivity, bioavailability and pharmacokinetics for rational optimization of new therapeutics.