Structural insights into the agonist activity of the nonpeptide modulator JR14a on C3aR

作者：Ping Luo, Wenwen Xin, Shimeng Guo, X. H. Li, Qing Zhang, Youwei Xu, Xinheng He, Yue Wang, Wenjia Fan, Qingning Yuan, Kai Wu, Wen Hu, Youwen Zhuang, H. Eric Xu, Xin Xie · 发表于：Cell Discovery · 年份：2025 · DOI：10.1038/s41421-024-00765-x · 被引用次数：6 · 研究领域：Adenosine and Purinergic Signaling、Receptor Mechanisms and Signaling、Neuropeptides and Animal Physiology

The complement system, a key component of innate immunity, remains inactive under normal conditions but activates in response to pathogens or antigen–antibody complexes, enhancing immune responses and maintaining tissue homeostasis 1 . Activation of the complement cascade produces anaphylatoxins like C3a and C5a, which regulate inflammatory and immune responses via their respective G protein-coupled receptors (GPCRs) 2 , 3 . Recent structural studies have elucidated the activation of these pathways 4 , 5 . Peptide ligands targeting C3aR are limited by their instability and administration route, hindering their therapeutic potential 6 , especially for the C3aR signaling-regulated neurodegenerative diseases and other disorders 7 . In contrast, small-molecule ligands offer enhanced stability and oral bioavailability, making them more useful for in vivo studies of C3aR and future clinical applications. However, only a few small-molecule ligands of C3aR, including SB290157, BR103 and JR14a, have been discovered. SB290157 and JR14a were reported as C3aR antagonists 8 , 9 , whereas BR103 is a full agonist 10 , despite their minimal structural differences (Supplementary Fig. S1a ).