Disconnect between signalling potency and in vivo ef fi cacy of pharmacokinetically optimised biased glucagon-like peptide-1 receptor agonists
Disconnect between signalling potency and in vivo ef fi cacy of pharmacokinetically optimised biased glucagon-like peptide-1 receptor agonists
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DOI：
10.1016/j.molmet.2020.100991
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发表时间：
2020-07-01
影响因子：
8.1
通讯作者：
Jones, Ben
中科院分区：
文献类型：
--
作者：
Lucey, Maria;Pickford, Philip;Jones, Ben
本研究的目的是确定如何代谢动力学有利的酰化影响胰高血糖素样肽-1受体（GLP-1 R）的信号偏差，贩运，抗高血糖症的疗效，和食欲suppression.MethodsIn体外信号反应进行了测量，使用生物化学和生物传感器测定。通过共聚焦显微镜和扩散增强共振能量转移测定GLP-1 R转运。药代动力学，glucoregulatory作用，食欲抑制测定在急性，亚慢性和慢性设置在mice.ResultsA C-末端酰化配体，[F1，G40，K41. C16二酸]exendin-4，被确定为无法检测的β-arrestin招聘和GLP-1 R内化。取决于所使用的细胞系统，这种分子是高达1000倍的效力比比较[D3，G40，K41。C16二酸]exendin-4的环AMP信号，但相当更effectivein体内，特别是葡萄糖regulation. ConclusionsC-末端酰化偏向GLP-1 R激动剂增加其有利于cAMP生产的信号偏差的程度，并提高其治疗潜力。
ObjectiveThe objective of this study was to determine how pharmacokinetically advantageous acylation impacts on glucagon-like peptide-1 receptor (GLP-1R) signal bias, trafficking, anti-hyperglycaemic efficacy, and appetite suppression.MethodsIn vitro signalling responses were measured using biochemical and biosensor assays. GLP-1R trafficking was determined by confocal microscopy and diffusion-enhanced resonance energy transfer. Pharmacokinetics, glucoregulatory effects, and appetite suppression were measured in acute, sub-chronic, and chronic settings in mice.ResultsA C-terminally acylated ligand, [F1,G40,K41.C16 diacid]exendin-4, was identified that showed undetectable β-arrestin recruitment and GLP-1R internalisation. Depending on the cellular system used, this molecule was up to 1000-fold less potent than the comparator [D3,G40,K41.C16 diacid]exendin-4 for cyclic AMP signalling, yet was considerably more effectivein vivo, particularly for glucose regulation.ConclusionsC-terminal acylation of biased GLP-1R agonists increases their degree of signal bias in favour of cAMP production and improves their therapeutic potential.