| 著者 |
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.
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| 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.
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