Publications 2025

De novo discovery of cyclic peptide inhibitors of IL-11 signaling

Cover of Bioorganic Medicinal Chemistry Journal

Sam Lear, Rosalba Tafi, Valentina A. Di Biasio, Petro Halkowycz, Ruhi Kamran, Joanne Miura, Tony S. Gibson, Jing Li, Bertram Bleck, Claudia Dall’Armi, Anna Demartis, Antoine Henninot (2025). Bioorganic & Medicinal Chemistry, Volume 119, 2025, 118017, ISSN 0968-0896, https://doi.org/10.1016/j.bmc.2024.118017.

Unlocking New Avenues for IL-11 Therapeutics

Interleukin-11 (IL-11), a member of the cytokine family, has been implicated in various disease pathologies, including pulmonary, hepatic, cardiovascular, renal, and intestinal disorders, as well as oncogenesis. Given its pro-inflammatory and pro-fibrotic roles, IL-11 has emerged as a promising target for therapeutic intervention.

While antibody-based IL-11 inhibitors are currently in Phase I/II clinical trials, small molecule and peptide-based inhibitors could offer advantages in tissue penetration, manufacturability, and cost-effectiveness. However, there is a significant gap in the availability of chemical inhibitors in the literature.

As part of a broader collaborative effort, IRBM contributed to the application of phage display technology to identify potent cyclic peptides targeting IL-11 and its receptor IL-11Rα.

Discovery of High-Affinity Peptide Inhibitors

Through a rigorous biopanning campaign, multiple cyclic peptides were identified by the collaborative research team, capable of binding IL-11 or IL-11Rα with high affinity. Among these, one peptide demonstrated exceptional binding characteristics:

  • Affinity: KD of 140 nM for IL-11
  • Inhibitory Activity: Ki of 300 nM in an AlphaLISA receptor-ligand inhibition assay
  • Mechanism: Prevents IL-11/IL-11Rα dimerization, a crucial step in signal transduction

To further enhance potency, an extensive alanine scanning effort was carried out to identify critical residues for binding. This led to the development of an optimized peptide lead exhibiting an improved Ki of 180 nM, making it at least 70-fold more potent than previously reported IL-11 inhibitors.

Graphical Abstract

Implications for Drug Development

The discovery of de novo peptide inhibitors offers multiple advantages for IL-11-targeted drug development:

  • Enhanced Specificity: The cyclic peptides selectively bind IL-11, reducing off-target effects.
  • Improved Safety Profile: Unlike receptor-targeting strategies, ligand-binding inhibitors may present a differentiated and potentially safer therapeutic approach.
  • Scalability & Manufacturability: Peptide-based therapies are often more cost-effective to produce compared to monoclonal antibodies.

The remarkable affinity (140 nM) achieved by our initial phage display hit, even before affinity maturation, underscores the power of phage display in drug discovery.

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Phage display remains a powerful tool in drug discovery, enabling the identification of high-affinity peptide and antibody therapeutics. If you are exploring novel inhibitors for cytokines or other challenging targets, our phage display services can help accelerate your research.

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