Human interleukin-1β (hIL-1β) is a pro-inflammatory cytokine implicated in various diseases. While hIL-1β-directed antibodies have shown clinical benefits, an orally available low-molecular-weight antagonist remains elusive. This research describes the discovery of a low-molecular-weight hIL-1β antagonist that blocks its interaction with the IL-1R1 receptor. Optimized from a low-affinity fragment, compound (S)-2 exhibits single-digit micromolar activity in various assays. X-ray analysis reveals an allosteric mechanism involving a novel binding site on hIL-1β. The compound effectively antagonizes hIL-1β function in cells, including primary human fibroblasts, suggesting its potential for therapeutic development.

Ulrich Hommel, Konstanze Hurth, Jean-Michel Rondeau, Anna Vulpetti, Daniela Ostermeier, Andreas Boettcher, Jacob Peter Bräy, Michael Hediger, Sylvie Lehmann, Elke Koch, Anke Blechschmidt, Rina Yamamoto, Valentina Tundo Dottorello, Sandra Haenni-Holzinger, Christian Kaiser, Philipp Lehr, Andreas Lingel, Luca Muredu, Christian Schleberger, Jutta Blank, Paul Ramage, Felix Freuler, Joerg Eder, Frédéric Bornancin