Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan.
Immunobiology, Graduate School of Medical Life Science, Yokohama City University, Yokohama, 230-0045, Japan.
Nat Commun. 2024 Jul 19;15(1):5743. doi: 10.1038/s41467-024-49893-8.
Sphingosine 1-phosphate receptor 1 (S1PR1), a G protein-coupled receptor, is required for lymphocyte trafficking, and is a promising therapeutic target in inflammatory diseases. Here, we synthesize a competitive S1PR1 antagonist, KSI-6666, that effectively suppresses pathogenic inflammation. Metadynamics simulations suggest that the interaction of KSI-6666 with a methionine residue Met124 in the ligand-binding pocket of S1PR1 may inhibit the dissociation of KSI-6666 from S1PR1. Consistently, in vitro functional and mutational analyses reveal that KSI-6666 causes pseudoirreversible inhibition of S1PR1, dependent on the Met124 of the protein and substituents on the distal benzene ring of KSI-6666. Moreover, in vivo study suggests that this pseudoirreversible inhibition is responsible for the persistent activity of KSI-6666.
鞘氨醇 1-磷酸受体 1（S1PR1）是一种 G 蛋白偶联受体，对于淋巴细胞的迁移是必需的，并且是炎症性疾病中有前途的治疗靶点。在这里，我们合成了一种竞争性 S1PR1 拮抗剂 KSI-6666，它能有效抑制致病性炎症。元动力学模拟表明，KSI-6666 与 S1PR1 配体结合口袋中蛋氨酸残基 Met124 的相互作用可能抑制 KSI-6666 与 S1PR1 的解离。一致地，体外功能和突变分析表明，KSI-6666 导致 S1PR1 的伪不可逆抑制，这依赖于蛋白质的 Met124 和 KSI-6666 远端苯环上的取代基。此外，体内研究表明，这种伪不可逆抑制是 KSI-6666 持续活性的原因。
