Department of Chemistry , University of Oxford , Mansfield Road Oxford OX1 3TA , U.K.
Sir William Dunn School of Pathology , University of Oxford , South Parks Road , Oxford OX1 3RE , U.K.
ACS Chem Biol. 2019 Sep 20;14(9):2055-2064. doi: 10.1021/acschembio.9b00533. Epub 2019 Sep 10.
GPR84 is an orphan G-protein-coupled receptor that is expressed on immune cells and implicated in several inflammatory diseases. The validation of GPR84 as a therapeutic target is hindered by the narrow range of available chemical tools and consequent poor understanding of GPR84 pathophysiology. Here we describe the discovery and characterization of DL-175, a potent, selective, and structurally novel GPR84 agonist and the first to display significantly biased signaling across GPR84-overexpressing cells, primary murine macrophages, and human U937 cells. By comparing DL-175 with reported GPR84 ligands, we show for the first time that biased GPR84 agonists have markedly different abilities to induce chemotaxis in human myeloid cells, while causing similar levels of phagocytosis enhancement. This work demonstrates that biased agonism at GPR84 enables the selective activation of functional responses in immune cells and delivers a high-quality chemical probe for further investigation.
GPR84 是一种孤儿 G 蛋白偶联受体，表达于免疫细胞，与多种炎症性疾病相关。由于可用的化学工具范围狭窄，对 GPR84 病理生理学的了解也较差，因此 GPR84 作为治疗靶点的验证受到阻碍。本文描述了 DL-175 的发现和特性，DL-175 是一种强效、选择性且结构新颖的 GPR84 激动剂，也是首个在过表达 GPR84 的细胞、原代小鼠巨噬细胞和人 U937 细胞中显示出显著信号偏倚的激动剂。通过将 DL-175 与已报道的 GPR84 配体进行比较，我们首次表明，具有信号偏向性的 GPR84 激动剂在诱导人髓样细胞趋化方面具有显著不同的能力，同时引起类似水平的吞噬增强。这项工作表明，GPR84 的偏性激动作用能够选择性地激活免疫细胞中的功能反应，并提供了一种高质量的化学探针，用于进一步研究。
