Discovery of a selective and biologically active low-molecular weight antagonist of human interleukin-1β

Ulrich Hommel (), Konstanze Hurth (), Jean-Michel Rondeau, Anna Vulpetti, Daniela Ostermeier, Andreas Boettcher, Jacob Peter Brady, Michael Hediger, Sylvie Lehmann, Elke Koch, Anke Blechschmidt, Rina Yamamoto, Valentina Tundo Dottorello, Sandra Haenni-Holzinger, Christian Kaiser, Philipp Lehr, Andreas Lingel, Luca Mureddu, Christian Schleberger, Jutta Blank, Paul Ramage, Felix Freuler, Joerg Eder and Frédéric Bornancin ()
Additional contact information
Ulrich Hommel: Novartis Campus
Konstanze Hurth: Novartis Campus
Jean-Michel Rondeau: Novartis Campus
Anna Vulpetti: Novartis Campus
Daniela Ostermeier: Novartis Campus
Andreas Boettcher: Novartis Campus
Jacob Peter Brady: 250 Massachusetts Avenue
Michael Hediger: Novartis Campus
Sylvie Lehmann: Novartis Campus
Elke Koch: Novartis Campus
Anke Blechschmidt: Novartis Campus
Rina Yamamoto: Novartis Campus
Valentina Tundo Dottorello: Novartis Campus
Sandra Haenni-Holzinger: Novartis Campus
Christian Kaiser: Novartis Campus
Philipp Lehr: Novartis Campus
Andreas Lingel: Novartis Campus
Luca Mureddu: University of Leicester
Christian Schleberger: Novartis Campus
Jutta Blank: Novartis Campus
Paul Ramage: Novartis Campus
Felix Freuler: Novartis Campus
Joerg Eder: Novartis Campus
Frédéric Bornancin: Novartis Campus

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Human interleukin-1β (hIL-1β) is a pro-inflammatory cytokine involved in many diseases. While hIL-1β directed antibodies have shown clinical benefit, an orally available low-molecular weight antagonist is still elusive, limiting the applications of hIL-1β-directed therapies. Here we describe the discovery of a low-molecular weight hIL-1β antagonist that blocks the interaction with the IL-1R1 receptor. Starting from a low affinity fragment-based screening hit 1, structure-based optimization resulted in a compound (S)-2 that binds and antagonizes hIL-1β with single-digit micromolar activity in biophysical, biochemical, and cellular assays. X-ray analysis reveals an allosteric mode of action that involves a hitherto unknown binding site in hIL-1β encompassing two loops involved in hIL-1R1/hIL-1β interactions. We show that residues of this binding site are part of a conformationally excited state of the mature cytokine. The compound antagonizes hIL-1β function in cells, including primary human fibroblasts, demonstrating the relevance of this discovery for future development of hIL-1β directed therapeutics.

Date: 2023
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DOI: 10.1038/s41467-023-41190-0

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