Peptide hormone-receptor interactions serve as critical regulators of metabolic homeostasis, a paradigm exemplified by the clinical efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists. Building upon this framework, strategic design has yielded unimolecular dual and triple agonists targeting GLP-1R, glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon receptor (GcgR), leveraging the sequence homology within the cognate native ligands of the class B G protein-coupled receptor (GPCR) family. However, the integration of Y2 receptor (Y2R) agonism─engaged by peptide YY (PYY) and belonging to the structurally divergent class A GPCR family─has remained an unaddressed challenge due to the topological and sequence disparities between these receptor classes. Y2R activation plays a pivotal role in appetite suppression, potentiating the metabolic benefits conferred by GLP-1R, GIPR, and GcgR agonism. Here, we report first-in-class, unprecedented tetra-agonists with high potency at GLP-1R, GIPR, GcgR, and Y2R. The chimeric peptides overcome the intrinsic sequence constraints imposed by class A and class B GPCR divergence, demonstrating the feasibility of rationally designed agonism mediated by single agents across receptor families. Lipidation of this template is well tolerated enhancing the promise of therapeutic viability. Furthermore, we show that biased agonism at GLP-1R selectively boosts cyclic AMP (cAMP) signaling while minimizing β-arrestin recruitment, thereby decoupling receptor desensitization from metabolic efficacy. Additionally, we introduce a tunable framework to modulate β-arrestin engagement without compromising cAMP potency, providing insight into the fine-tuning of GPCR-mediated signaling for next-generation peptide therapeutics.

中文翻译：

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单分子四受体激动剂的分子设计

肽激素-受体相互作用是代谢稳态的关键调节因子，胰高血糖素样肽-1 （GLP-1） 受体激动剂的临床疗效就是例证。基于这一框架，战略设计产生了靶向 GLP-1R、葡萄糖依赖性促胰岛素多肽受体 （GIPR） 和胰高血糖素受体 （GcgR） 的单分子双联和三重激动剂，利用 B 类 G 蛋白偶联受体 （GPCR） 家族同源天然配体内的序列同源性。然而，由于这些受体类别之间的拓扑和序列差异，Y2 受体 （Y2R） 激动作用的整合——由肽 YY （PYY） 参与并属于结构不同的 A 类 GPCR 家族——仍然是一个未解决的挑战。Y2R 激活在食欲抑制中起关键作用，增强 GLP-1R、GIPR 和 GcgR 激动剂赋予的代谢益处。在这里，我们报道了同类首创、前所未有的四激动剂，在 GLP-1R、GIPR、GcgR 和 Y2R 中具有高效力。嵌合肽克服了 A 类和 B 类 GPCR 分歧施加的内在序列限制，证明了由跨受体家族的单一药物介导的合理设计激动的可行性。该模板的脂质化耐受性良好，增强了治疗活力的前景。此外，我们表明 GLP-1R 的偏倚激动选择性地增强环 AMP （cAMP） 信号传导，同时最大限度地减少 β-arrestin 募集，从而将受体脱敏与代谢功效脱钩。此外，我们引入了一个可调框架来调节 β-arrestin 结合而不影响 cAMP 效力，从而深入了解 GPCR 介导的信号转导的微调，用于下一代肽治疗。