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

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  • Yuya Maruyama

    (RIKEN Center for Integrative Medical Sciences
    Yokohama City University
    4365-1 Hotaka-Kashiwabara)

  • 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
    Yokohama City University)

  • Kano Namiki

    (RIKEN Center for Integrative Medical Sciences
    Yokohama City University)

  • Naho Hagiwara

    (RIKEN Center for Integrative Medical Sciences)

  • Maki Miyauchi

    (RIKEN Center for Integrative Medical Sciences
    Yokohama City University)

  • Takahisa Miyao

    (RIKEN Center for Integrative Medical Sciences)

  • Tatsuya Ishikawa

    (RIKEN Center for Integrative Medical Sciences
    Yokohama City University)

  • Kenta Horie

    (RIKEN Center for Integrative Medical Sciences)

  • Mio Hayama

    (RIKEN Center for Integrative Medical Sciences
    Yokohama City University)

  • Nobuko Akiyama

    (RIKEN Center for Integrative Medical Sciences
    Yokohama City University)

  • Takatsugu Hirokawa

    (1-1-1 Tennodai
    1-1-1 Tennodai)

  • Taishin Akiyama

    (RIKEN Center for Integrative Medical Sciences
    Yokohama City University)

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.

Suggested Citation

  • Yuya Maruyama & Yusuke Ohsawa & Takayuki Suzuki & Yuko Yamauchi & Kohsuke Ohno & Hitoshi Inoue & Akitoshi Yamamoto & Morimichi Hayashi & Yuji Okuhara & Wataru Muramatsu & Kano Namiki & Naho Hagiwara &, 2024. "Pseudoirreversible inhibition elicits persistent efficacy of a sphingosine 1-phosphate receptor 1 antagonist," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49893-8
    DOI: 10.1038/s41467-024-49893-8
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    1. David A. Sykes & Holly Moore & Lisa Stott & Nicholas Holliday & Jonathan A. Javitch & J. Robert Lane & Steven J. Charlton, 2017. "Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
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