Anna Vulpetti; Jean-Michel Rondeau; Marie-Hélène Bellance; Jutta Blank; Ralf Boesch; Andreas Boettcher; Frédéric Bornancin; Sylvia Buhr; Lauren E. Connor; Christoph E. Dumelin; Esser, Oliver; Michael Hediger; Hintermann, Samuel; Ulrich Hommel; Elke Koch; Guillaume Lapointe; Lukas Leder; Sylvie Lehmann; Philipp Lehr; Peter Meier; Lionel Muller; Daniela Ostermeier; Paul Ramage; Sihame Schiebel-Haddad; Alexander Baxter Smith; Aleksandar Stojanovic; Juraj Velcicky; Rina Yamamoto; Konstanze Hurth
J. Med. Chem., 2024, 67(10), 8141–8160
https://doi.org/10.1021/acs.jmedchem.4c00240

Abstract

Human interleukin-1β (IL-1β) is a pro-inflammatory cytokine that plays a critical role in the regulation of the immune response and the development of various inflammatory diseases. In this publication, we disclose our efforts toward the discovery of IL-1β binders that interfere with IL-1β signaling. To this end, several technologies were used in parallel, including fragment-based screening (FBS), DNA-encoded library (DEL) technology, peptide discovery platform (PDP), and virtual screening. The utilization of distinct technologies resulted in the identification of new chemical entities exploiting three different sites on IL-1β, all of them also inhibiting the interaction with the IL-1R1 receptor. Moreover, we identified lysine 103 of IL-1β as a target residue suitable for the development of covalent, low-molecular-weight IL-1β antagonists.