Design of Bicyclic Peptide Tandems Mimicking the Homodimeric GDF15 Protein to Inhibit GDF15–GFRaL–RET Complex Cell Signaling
The GDF15-GFRaL-RET signaling complex is involved in a broad range of disease states, with agonistic action of GDF15 affecting metabolism and body weight control, while inhibition is indicated in cancer and wasting disorders like cachexia. Here, we describe the discovery of the peptide inhibitors of the GDF15-GFRaL protein-protein interaction to prevent RET-induced signaling using both a structure-guided design and a phage display approach. Phage display provided bicyclic peptide hits with high affinity for GFRaL, and these were dimerized to mimic the bidentate interaction of homodimeric GDF15. Guided by structural data, the monomeric peptides were converted into tandem Bicycle molecules with picomolar affinities, similar to that of the endogenous GDF15 ligand. These dimerized protein mimetics inhibited cell signaling in a functional assay and showed improved pharmacokinetic properties compared with their monomeric counterparts. This is the first example of a homodimeric Bicycle molecule inhibiting receptor complex formation, thereby antagonizing the intracellular signaling response.
Authors
- Sophie Watcham (ORCID: https://orcid.org/0000-0001-5817-9275)
- Anaïs F. M. Noisier (ORCID: https://orcid.org/0000-0002-6949-5764)
- Gemma Mudd (ORCID: https://orcid.org/0000-0002-5075-1625)
- Malin Lemurell (ORCID: https://orcid.org/0000-0001-8718-9421)
- Michael J. Skynner
- Maria Fritsch
- Yafeng Xue (ORCID: https://orcid.org/0000-0002-7526-8672)
- Robert Roth (ORCID: https://orcid.org/0000-0002-7084-6947)
- Johan Broddefalk
- Liuhong Chen (ORCID: https://orcid.org/0000-0003-1776-3146)
- Jenny Sandmark (ORCID: https://orcid.org/0000-0002-3237-2429)
- Jenny Gunnarsson
- Cecilia Kankkonen (ORCID: https://orcid.org/0000-0001-6547-1792)
- Fredrik Edfeldt (ORCID: https://orcid.org/0000-0003-4049-1070)
- Ulrik Jurva
- J.M. Wandzik (ORCID: https://orcid.org/0000-0002-4033-1790)
- Andrey I. Frolov (ORCID: https://orcid.org/0000-0001-9801-3253)
- Janna M. Bigalke (ORCID: https://orcid.org/0000-0002-3473-4390)
- David J. Craik (ORCID: https://orcid.org/0000-0003-0007-6796)
- Katerine Van Rietschoten (ORCID: https://orcid.org/0000-0002-0360-8244)
- Margareta Ek (ORCID: https://orcid.org/0000-0001-8226-8112)
- Sunay V. Chankeshwara (ORCID: https://orcid.org/0000-0001-8886-170X)
- Louise Barlind
- Anna Backmark (ORCID: https://orcid.org/0000-0001-8973-0488)
- Helen C. Harrison
- Carina Johansson
Institutions
- Australian Research Council (AU)
- The University of Queensland (AU)
- Granta Design (United Kingdom) (GB)
- AstraZeneca (Netherlands) (NL)
- AstraZeneca (Japan) (JP)
- AstraZeneca (Finland) (FI)
- ARC Centre of Excellence for Innovations in Peptide and Protein Science (AU)
- AstraZeneca (Italy) (IT)
- AstraZeneca (Sweden) (SE)
- AstraZeneca (Germany) (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-10-09
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01378
- Citations
- 1
- Primary Topic
- GDF15 and Related Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 1.67