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

Yuya Maruyama, Yusuke Ohsawa, Takayuki Suzuki, Yuko Yamauchi, Kohsuke Ohno, Hitoshi Inoue, Akitoshi Yamamoto, Morimichi Hayashi, Yuji Okuhara, Wataru Muramatsu, Kano Namiki, Naho Hagiwara, Maki Miyauchi, Takahisa Miyao, Tatsuya Ishikawa, Kenta Horie, Mio Hayama, Nobuko Akiyama, Takatsugu Hirokawa and Taishin Akiyama ()
Additional contact information
Yuya Maruyama: RIKEN Center for Integrative Medical Sciences
Yusuke Ohsawa: 4365-1 Hotaka-Kashiwabara
Takayuki Suzuki: 4365-1 Hotaka-Kashiwabara
Yuko Yamauchi: 4365-1 Hotaka-Kashiwabara
Kohsuke Ohno: 4365-1 Hotaka-Kashiwabara
Hitoshi Inoue: 4365-1 Hotaka-Kashiwabara
Akitoshi Yamamoto: 4365-1 Hotaka-Kashiwabara
Morimichi Hayashi: 4365-1 Hotaka-Kashiwabara
Yuji Okuhara: 4365-1 Hotaka-Kashiwabara
Wataru Muramatsu: RIKEN Center for Integrative Medical Sciences
Kano Namiki: RIKEN Center for Integrative Medical Sciences
Naho Hagiwara: RIKEN Center for Integrative Medical Sciences
Maki Miyauchi: RIKEN Center for Integrative Medical Sciences
Takahisa Miyao: RIKEN Center for Integrative Medical Sciences
Tatsuya Ishikawa: RIKEN Center for Integrative Medical Sciences
Kenta Horie: RIKEN Center for Integrative Medical Sciences
Mio Hayama: RIKEN Center for Integrative Medical Sciences
Nobuko Akiyama: RIKEN Center for Integrative Medical Sciences
Takatsugu Hirokawa: 1-1-1 Tennodai
Taishin Akiyama: RIKEN Center for Integrative Medical Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49893-8

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