Functional screening and rational design of compounds targeting GPR132 to treat diabetes

• DOI: 10.1038/s42255-023-00899-4
• Publication Date: 2023-09-28T16:02:03Z
• Authors: Jia-Le Wang; Xiao-Dong Dou; Jie Cheng; Ming-Xin Gao; Guo-Feng Xu; Wei Ding; Jin-Hui Ding; Yu Li; Si-Han Wang; Zhao-Wei Ji; Xin-Yi Zhao; Tong-Yu Huo; Cai-Fang Zhang; Ya-Meng Liu; Xue-Ying Sha; Jia-Rui Gao; Wen-Hui Zhang; Yong Hao; Cheng Zhang; Jin-Peng Sun; Ning Jiao; Xiao Yu
• Keywords: Mice; Islets of Langerhans; Diabetes Mellitus, Type 2; Cryoelectron Microscopy; Animals; Receptors, G-Protein-Coupled; Signal Transduction

Chronic inflammation due to islet-residing macrophages plays key roles in the development of type 2 diabetes mellitus. By systematically profiling intra-islet lipid-transmembrane receptor signalling in islet-resident macrophages, we identified endogenous 9(S)-hydroxy-10,12-octadecadienoic acid-G-protein-coupled receptor 132 (GPR132)-Gi signalling as a significant contributor to islet macrophage reprogramming and found that GPR132 deficiency in macrophages reversed metabolic disorders in mice fed a high-fat diet. The cryo-electron microscopy structures of GPR132 bound with two endogenous agonists, N-palmitoylglycine and 9(S)-hydroxy-10,12-octadecadienoic acid, enabled us to rationally design both GPR132 agonists and antagonists with high potency and selectivity through stepwise translational approaches. We ultimately identified a selective GPR132 antagonist, NOX-6-18, that modulates macrophage reprogramming within pancreatic islets, decreases weight gain and enhances glucose metabolism in mice fed a high-fat diet. Our study not only illustrates that intra-islet lipid signalling contributes to islet macrophage reprogramming but also provides a broadly applicable strategy for the identification of important G-protein-coupled receptor targets in pathophysiological processes, followed by the rational design of therapeutic leads for refractory diseases such as diabetes.