ArticleNature communications2023
Discovery of a selective and biologically active low-molecular weight antagonist of human interleukin-1β.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 25 citations in OpenAlex.
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- Exploring the Structural Basis of Cryptic Pocket Formation Driven by Extensive Protein Conformational Changes in Drug Targets.Journal of chemical theory and computation · 2026Article
- Antagonist Binding Actively Disrupts Interleukin-1 Receptor Dynamics to Block Co-receptor Recruitment.Computational and structural biotechnology journal · 2026Article
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- Inflammasome components as new therapeutic targets in inflammatory disease.Nature reviews. Immunology · 2025Review
- Targeting interleukin-1 signaling for renoprotection.Frontiers in immunology · 2025Review
- Doxorubicin-induced nephrotoxicity: the protective role of a standardized ethanolic extract ofFrontiers in pharmacology · 2025Article
- Advancing Target Validation and Ligandability Assessment: Fragment Screening viaMethods in molecular biology (Clifton, N.J.) · 2025Article
- SWISH-X, an Expanded Approach to Detect Cryptic Pockets in Proteins and at Protein-Protein Interfaces.Journal of chemical theory and computation · 2024Article
- Exploring the Wound Healing Potential of aPharmaceutics · 2024Article
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- Current perspectives in the management of sepsis and septic shock.Frontiers in medicine · 2024Review
Corrections and comments
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Authors and funding
24 authors at 2 institutions in 2 countries.
Funding
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.
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Registered trials
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