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Discovery of selective low molecular weight interleukin-36 receptor antagonists by encoded library technologies

Author

Listed:
  • Juraj Velcicky

    (Novartis Campus)

  • Gregor Cremosnik

    (Novartis Campus)

  • Clemens Scheufler

    (Novartis Campus)

  • Peter Meier

    (Novartis Campus)

  • Emmanuelle Wirth

    (Novartis Campus)

  • Richard Felber

    (Novartis Campus)

  • Paul Ramage

    (Novartis Campus)

  • Michael Schaefer

    (Novartis Campus)

  • Christian Kaiser

    (Novartis Campus)

  • Sylvie Lehmann

    (Novartis Campus)

  • Raphaela Kutil

    (Novartis Campus)

  • Sandra Singeisen

    (Novartis Campus)

  • Dorothee Mueller-Ristig

    (Novartis Campus)

  • Simone Popp

    (Novartis Campus)

  • Regis Cebe

    (Novartis Campus)

  • Philipp Lehr

    (Novartis Campus)

  • Klemens Kaupmann

    (Novartis Campus)

  • Paulus Erbel

    (Novartis Campus)

  • Till A. Röhn

    (Novartis Campus)

  • Jerome Giovannoni

    (Novartis Campus)

  • Christoph E. Dumelin

    (Novartis Campus)

  • Georg Martiny-Baron

    (Novartis Campus)

Abstract

Interleukin-36 receptor (IL-36R), belonging to the IL-1 receptor family, is crucial for host defense and tissue repair. Targeting cytokine receptors with low molecular weight (LMW) compounds remains challenging due to their interaction with the large surface area of cytokine. In this study, two encoded library technologies are used to identify LMW molecules binding to IL-36R’s extracellular domain. The mRNA-based display technique identifies 36R-P138, a macrocyclic peptide blocking IL-36R signaling. Importantly, its optimized analog (36R-P192) also effectively suppresses expression of marker genes induced by IL-36 in human skin biopsies. DNA encoded libraries (DEL) screening delivers 36R-D481, a high affinity LMW IL-36R binder, effectively inhibiting IL-36 signaling. X-ray crystallography analysis reveals that both the cyclic peptide and DEL-compound bind to the IL-36R’s D1 domain, potentially disrupting IL-36 cytokine binding. This study demonstrates that it is possible to target a cytokine receptor within the IL-1 receptor family using a small molecule (

Suggested Citation

  • Juraj Velcicky & Gregor Cremosnik & Clemens Scheufler & Peter Meier & Emmanuelle Wirth & Richard Felber & Paul Ramage & Michael Schaefer & Christian Kaiser & Sylvie Lehmann & Raphaela Kutil & Sandra S, 2025. "Discovery of selective low molecular weight interleukin-36 receptor antagonists by encoded library technologies," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56601-7
    DOI: 10.1038/s41467-025-56601-7
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    References listed on IDEAS

    as
    1. Herman Schreuder & Chantal Tardif & Susanne Trump-Kallmeyer & Adolfo Soffientini & Edoardo Sarubbi & Ann Akeson & Terry Bowlin & Stephen Yanofsky & Ronald W. Barrett, 1997. "A new cytokine-receptor binding mode revealed by the crystal structure of the IL-1 receptor with an antagonist," Nature, Nature, vol. 386(6621), pages 194-200, March.
    2. Guy P. A. Vigers & Lana J. Anderson & Patricia Caffes & Barbara J. Brandhuber, 1997. "Crystal structure of the type-I interleukin-1 receptor complexed with interleukin-1β," Nature, Nature, vol. 386(6621), pages 190-194, March.
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