2025年10月22日出版的《自然》杂志发表了明尼苏达大学Lauren M. Slosky小组的最新成果，他们的研究认为设计变构调节剂改变GPCR G蛋白亚型选择性。

然而，偏见的决定因素知之甚少，该课题组人员缺乏合理设计的分子来选择特定的G蛋白。以典型的A类GPCR神经紧张素受体1 （NTSR1）为主题，研究团队发现结合到细胞内GPCR -传感器界面的小分子通过亚型特异性和可预测的机制改变G蛋白偶联，从而实现结构导向的药物设计。课题组人员发现细胞内的核心结合化合物SBI-553通过直接的分子间相互作用来改变NTSR1对G蛋白的偏好，促进或阻止与特定G蛋白亚型的结合。对SBI-553支架的修饰产生具有不同G蛋白选择性谱的变构调节剂。选择性谱是探针独立的，跨物种保守，并转化为体内活性的差异。他们的研究表明，G蛋白的选择性可以通过对单一化学支架的微小改变来调整，以靶向受体-换能器界面。

此外，考虑到这个口袋是广泛保守的，他们的发现可以提供一种适用于多种GPCR超家族的途径选择性药物发现策略。

研究人员表示，G蛋白偶联受体（GPCRs）通过16种Gα蛋白亚型和2种β-阻滞蛋白将细胞外信号转化为细胞内反应。偏向化合物——优先激活这些蛋白质子集的分子——更有选择性地参与与治疗相关的途径，并且有望成为比统一激活所有途径的化合物更安全、更有效的药物。

附：英文原文

Title: Designing allosteric modulators to change GPCR G protein subtype selectivity

Author: Moore, Madelyn N., Person, Kelsey L., Robleto, Valeria L., Alwin, Abigail R., Krusemark, Campbell L., Foster, Noah, Ray, Caroline, Inoue, Asuka, Jackson, Michael R., Sheedlo, Michael J., Barak, Lawrence S., Marron Fernandez de Velasco, Ezequiel, Olson, Steven H., Slosky, Lauren M.

Issue&Volume: 2025-10-22

Abstract: G-protein-coupled receptors (GPCRs) convert extracellular signals into intracellular responses by signalling through 16 subtypes of Gα proteins and two β-arrestin proteins. Biased compounds—molecules that preferentially activate a subset of these proteins—engage therapy-relevant pathways more selectively1 and promise to be safer, more effective medications than compounds that uniformly activate all pathways2. However, the determinants of bias are poorly understood, and we lack rationally designed molecules that select for specific G proteins. Here, using the prototypical class A GPCR neurotensin receptor 1 (NTSR1), we show that small molecules that bind to the intracellular GPCR–transducer interface change G protein coupling by subtype-specific and predictable mechanisms, enabling structure-guided drug design. We find that the intracellular, core-binding compound SBI-553 switches the G protein preference of NTSR1 through direct intermolecular interactions3,4,5, promoting or preventing association with specific G protein subtypes. Modifications to the SBI-553 scaffold produce allosteric modulators with distinct G protein selectivity profiles. Selectivity profiles are probe independent, conserved across species and translate to differences in activity in vivo. Our studies show that G protein selectivity can be tailored with small changes to a single chemical scaffold targeting the receptor–transducer interface. Moreover, given that this pocket is broadly conserved, our findings could provide a strategy for pathway-selective drug discovery that is applicable to the diverse GPCR superfamily.

DOI: 10.1038/s41586-025-09643-2

Source: https://www.nature.com/articles/s41586-025-09643-2