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

Juraj Velcicky (), Gregor Cremosnik, Clemens Scheufler, Peter Meier, Emmanuelle Wirth, Richard Felber, Paul Ramage, Michael Schaefer, Christian Kaiser, Sylvie Lehmann, Raphaela Kutil, Sandra Singeisen, Dorothee Mueller-Ristig, Simone Popp, Regis Cebe, Philipp Lehr, Klemens Kaupmann, Paulus Erbel, Till A. Röhn, Jerome Giovannoni, Christoph E. Dumelin and Georg Martiny-Baron ()
Additional contact information
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

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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 (

Date: 2025
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DOI: 10.1038/s41467-025-56601-7

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