Objective

The 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.

Methods

In 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.

Results

A 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 effective in vivo, particularly for glucose regulation.

Conclusions

C-terminal acylation of biased GLP-1R agonists increases their degree of signal bias in favour of cAMP production and improves their therapeutic potential.

中文翻译：

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药代动力学优化的胰高血糖素样肽 1 受体激动剂的信号传导效力与体内功效之间的脱节。

 客观的

本研究的目的是确定药代动力学上有利的酰化如何影响胰高血糖素样肽 1 受体 (GLP-1R) 信号偏差、运输、抗高血糖功效和食欲抑制。

 方法

使用生化和生物传感器测定来测量体外信号反应。 GLP-1R 运输通过共焦显微镜和扩散增强共振能量转移来测定。在小鼠的急性、亚慢性和慢性环境中测量药代动力学、葡萄糖调节作用和食欲抑制。

 结果

鉴定出 C 末端酰化配体 [F ¹ 、G ⁴⁰ 、K ⁴¹ .C16 二酸]exendin-4，其显示出不可检测的 β-抑制蛋白募集和 GLP-1R 内化。根据所使用的细胞系统，该分子对于环 AMP 信号传导的效力比比较剂 [D ³ 、G ⁴⁰ 、K ⁴¹ .C16 二酸]exendin-4 低 1000 倍，但在体内却显着更有效，特别是用于血糖调节。

 结论

偏向的 GLP-1R 激动剂的 C 末端酰化增加了其信号偏向程度，有利于 cAMP 的产生，并提高了其治疗潜力。