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Discovery of a selective and biologically active low-molecular weight antagonist of human IL-1b

Blank, Jutta, Blechschmidt, Anke, Boettcher, Andreas, Bornancin, Frederic, Brady, Jacob, Eder, Joerg, Freuler, Felix, Haenni-Holzinger, Sandra, Hediger, Michael, Hommel, Ulrich, Hurth, Konstanze, Kaiser, Christian, Koch, Elke, Lehmann, Sylvie, Lehr, Philipp, Lingel, Andreas, Ostermeier, Daniela, Ramage, Paul, Rondeau, Jean-Michel, Tundo Dottorello, Valentina, Vulpetti, Anna, Yamamoto, Rina, Mureddu, Luca and Schleberger, Christian (2023) Discovery of a selective and biologically active low-molecular weight antagonist of human IL-1b. Nature communications, 14. pp. 5497-5509.


Human interleukin-1b (hIL-1b) is a pro-inflammatory cytokine involved in many diseases. While hIL-1b directed antibodies have shown clinical benefit, an orally available low-molecular weight antagonist is still elusive, limiting the applications of hIL-1b-directed therapies. Here we describe the discovery of the first low-molecular weight hIL-1b 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-1b 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-1b encompassing two loops involved in hIL-1R1/hIL-1b interactions. We show that residues of this binding site are part of a conformationally excited state of the mature cytokine. The compound antagonizes hIL-1b function in cells, including primary human fibroblasts, demonstrating the relevance of this discovery for future development of novel hIL-1b directed therapeutics.

Item Type: Article
Date Deposited: 30 Sep 2023 00:45
Last Modified: 30 Sep 2023 00:45