Pseudoirreversible inhibition elicits persistent efficacy of a sphingosine 1-phosphate receptor 1 antagonist

• Published in: Nature communications Vol. 15; no. 1; pp. 5743 - 17
• Main Authors: Maruyama, Yuya, Ohsawa, Yusuke, Suzuki, Takayuki, Yamauchi, Yuko, Ohno, Kohsuke, Inoue, Hitoshi, Yamamoto, Akitoshi, Hayashi, Morimichi, Okuhara, Yuji, Muramatsu, Wataru, Namiki, Kano, Hagiwara, Naho, Miyauchi, Maki, Miyao, Takahisa, Ishikawa, Tatsuya, Horie, Kenta, Hayama, Mio, Akiyama, Nobuko, Hirokawa, Takatsugu, Akiyama, Taishin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19-07-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 119/118; 13; 13/106; 13/31; 631/114; 631/154/309; 631/250/256; 631/45/612/194; 64/60; 96/31; Animals; Benzene; Competition; Heart rate; HEK293 Cells; Humanities and Social Sciences; Humans; In vivo methods and tests; Inflammation - drug therapy; Inflammation - metabolism; Inflammatory diseases; Leukocytes; Ligands; Lymphocytes; Male; Methionine; Mice; Mice, Inbred C57BL; multidisciplinary; Protein transport; Proteins; Receptors; Science; Science (multidisciplinary); Sphingosine 1-phosphate; Sphingosine-1-Phosphate Receptors - antagonists & inhibitors; Sphingosine-1-Phosphate Receptors - metabolism; Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• 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.
Sphingosine 1-phosphate receptor 1 (S1PR1) is crucial for lymphocyte trafficking and a target in inflammatory diseases. Here, authors discover KSI6666, a competitive S1PR1 antagonist that suppresses inflammation through pseudoirreversible inhibition.