2025年6月23日，Atrogi ABTore Bengtsson课题组在《细胞》杂志发表论文，宣布他们的研究开发出了GRK偏向肾上腺素能激动剂治疗2型糖尿病和肥胖。

利用基于配体的虚拟筛选和化学进化，该团队开发了β₂AR的通路选择性激动剂，这种激动剂倾向于GRK偶联。这些化合物在高血糖和肥胖的临床前模型中表现良好，与标准β2受体激动剂和肠促胰岛素模拟剂相比，它们对心脏和细胞的副作用更低。

此外，该候选药物在安慰剂对照临床试验中表现出良好的药代动力学和耐受性。GRK偏倚的β₂AR部分激动剂是治疗2型糖尿病和肥胖的有希望的口服替代注射促肠促胰岛素的药物。

研究人员表示，G蛋白偶联受体（GPCR）的偏向激动作用为更安全的药物提供了潜力。目前的努力已经探索了G蛋白和β-阻滞蛋白之间的平衡；然而，其他传导因子如GPCR激酶（GRKs）仍未得到充分研究。GRK2对于β2肾上腺素能受体（β₂AR）介导的葡萄糖摄取至关重要，但由于G_s/环AMP （cAMP）诱导的心脏副作用和β-骤停蛋白依赖性脱敏，β₂AR激动剂被认为是血糖管理的不良临床候选药物。

附：英文原文

Title: GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity

Author: Aikaterini Motso, Benjamin Pelcman, Anastasia Kalinovich, Nour Aldin Kahlous, Muhammad Hamza Bokhari, Nodi Dehvari, Carina Halleskog, Erik Waara, Jasper de Jong, Elizabeth Cheesman, Christine Kallenberg, Gopala Krishna Yakala, Praerona Murad, Erika Wetterdal, Pia Andersson, Sten van Beek, Anna Sandstrm, Diane Natacha Alleluia, Emanuela Talamonti, Sonia Youhanna, Pierre Sabatier, Claire Koenig, Sabine Willems, Aurino M. Kemas, Dana S. Hutchinson, Seungmin Ham, Lukas Grtz, Jan Voss, Jose G. Marchan-Alvarez, Martins Priede, Krista Jaunsleine, Jana Spura, Vadims Kovada, Linda Supe, Leigh A. Stoddart, Nicholas D. Holliday, Phillip T. Newton, Nicolas J. Pillon, Gunnar Schulte, Roger J. Summers, Ilga Mutule, Edgars Suna, Jesper V. Olsen, Peter Molenaar, Jens Carlsson, Volker M. Lauschke, Shane C. Wright, Tore Bengtsson

Issue&Volume: 2025-06-23

Abstract: Biased agonism of G protein-coupled receptors (GPCRs) offers potential for safer medications. Current efforts have explored the balance between G proteins and β-arrestin; however, other transducers like GPCR kinases (GRKs) remain understudied. GRK2 is essential for β2 adrenergic receptor (β2AR)-mediated glucose uptake, but β2AR agonists are considered poor clinical candidates for glycemic management due to Gs/cyclic AMP (cAMP)-induced cardiac side effects and β-arrestin-dependent desensitization. Using ligand-based virtual screening and chemical evolution, we developed pathway-selective agonists of β2AR that prefer GRK coupling. These compounds perform well in preclinical models of hyperglycemia and obesity and demonstrate a lower potential for cardiac and muscular side effects compared with standard β2-receptor agonists and incretin mimetics, respectively. Furthermore, the lead candidate showed favorable pharmacokinetics and was well tolerated in a placebo-controlled clinical trial. GRK-biased β2AR partial agonists are thus promising oral alternatives to injectable incretin mimetics used in the treatment of type 2 diabetes and obesity.

DOI: 10.1016/j.cell.2025.05.042

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00630-0