RRC ID 81134
Author Maruyama Y, Ohsawa Y, Suzuki T, Yamauchi Y, Ohno K, Inoue H, Yamamoto A, Hayashi M, Okuhara Y, Muramatsu W, Namiki K, Hagiwara N, Miyauchi M, Miyao T, Ishikawa T, Horie K, Hayama M, Akiyama N, Hirokawa T, Akiyama T.
Title Pseudoirreversible inhibition elicits persistent efficacy of a sphingosine 1-phosphate receptor 1 antagonist.
Journal Nat Commun
Abstract 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.
Volume 15(1)
Pages 5743
Published 2024-7-19
DOI 10.1038/s41467-024-49893-8
PII 10.1038/s41467-024-49893-8
PMID 39030171
MeSH Animals HEK293 Cells Humans Inflammation / drug therapy Inflammation / metabolism Male Mice Mice, Inbred C57BL Sphingosine-1-Phosphate Receptors* / antagonists & inhibitors Sphingosine-1-Phosphate Receptors* / metabolism
Resource
Human and Animal Cells 293(RCB1637)