Global Research Technologies, Novo Nordisk Research Park, 2760, Maaloev, Denmark.
Global Drug Discovery, Novo Nordisk Research Park, 2760, Maaloev, Denmark.
Angew Chem Int Ed Engl. 2021 Apr 6;60(15):8268-8275. doi: 10.1002/anie.202016464. Epub 2021 Mar 1.
The two gut hormones GLP-1 and PYY , which are both secreted from the L-cells upon food stimuli, have a stronger inhibitory effect on food intake when they are combined, compared to their individual effects as single agonists. Although they are not homologous and share no sequence similarity, we show that a GLP-1 analogue can be designed to exhibit potent activity on both the Y and GLP-1 receptors. Dual acting hybrid analogues were realized by designing truncated and potent Y receptor PYY analogues, followed by integrating the critical residues into GLP-1. In this study, we show that one of these dual acting agonists acutely reduces food intake significantly more than the respective mono-agonist counterparts.
两种肠激素 GLP-1 和 PYY 都在食物刺激下从 L 细胞中分泌出来，与作为单一激动剂的单独作用相比，它们结合时对食物摄入的抑制作用更强。虽然它们不是同源的，也没有序列相似性，但我们表明，可以设计 GLP-1 类似物来对 Y 和 GLP-1 受体都表现出强大的活性。通过设计截断的和有效的 Y 受体 PYY 类似物来实现双重作用的混合类似物，然后将关键残基整合到 GLP-1 中。在这项研究中，我们表明，这些双重作用激动剂之一可显著急性地减少食物摄入，比各自的单激动剂对应物更为明显。
