Optimal Stapling of a Helical Peptide‐Foldamer Hybrid Using a <i>C</i>‐Terminal 4‐Mercaptoproline Enhances Protein Surface Recognition and Cellular Activity
Structural analysis of a co-crystal of a helically-folded peptide-foldamer hybrid in complex with hDM2 E3 ubiquitin ligase, revealed a unique orientation for the C-terminal proline with the pyrrolidine ring pointing backwards in the sequence, and suggested new opportunities for macrocyclization. In particular, we found that the C-terminal prolyl residue could be replaced by its (2S,4S)-4-mercaptoprolyl analogue for optimal bisthioether crosslinking with a cysteine residue installed at position 4 in the sequence. The resulting i,i+7 stapled peptide-foldamer is a high-affinity binder to hDM2, is cell permeable and restores the p53 signalling pathway in p53wt cancer cells. The co-crystal structure of hDM2 and the stapled peptide-foldamer hybrid was determined at 1.84 Å, fully validating the original design and further highlighting the potential of cis-4-mercaptoproline in the context of peptide and foldamer stapling.
Authors
- Abdel‐Majid Khatib (ORCID: https://orcid.org/0000-0001-6957-0384)
- Jérémie Buratto (ORCID: https://orcid.org/0000-0002-6730-336X)
- Emmanuelle Thinon (ORCID: https://orcid.org/0000-0001-9248-5655)
- Isabel Galeano-Otero (ORCID: https://orcid.org/0000-0003-3219-4201)
- Sébastien R. Goudreau (ORCID: https://orcid.org/0000-0002-2803-876X)
- Maxime Neuville
- Laura Mauran (ORCID: https://orcid.org/0000-0001-8278-618X)
- Morgane Pasco (ORCID: https://orcid.org/0000-0002-1556-2802)
- Gilles Guichard (ORCID: https://orcid.org/0000-0002-2584-7502)
- Brice Kauffmann (ORCID: https://orcid.org/0000-0002-2932-3255)
- Claire Saragaglia (ORCID: https://orcid.org/0000-0002-9686-8992)
- Bo Li (ORCID: https://orcid.org/0000-0003-4615-6898)
- Mathieu Bourgeais (ORCID: https://orcid.org/0000-0002-6347-2190)
- Laetitia Varajao
Institutions
- Centre National de la Recherche Scientifique (FR)
- Université de Bordeaux (FR)
- Inserm (FR)
- Technologies pour la Santé (FR)
- Bordeaux Population Health (FR)
- Chimie et Biologie des Membranes et des Nanoobjects (FR)
- ImmuPharma (France) (FR)
- Institut Européen de Chimie et Biologie (FR)
- Institut Polytechnique de Bordeaux (FR)
- BoRdeaux Institute of onCology (FR)
Publication Details
- Journal
- Chemistry - A European Journal
- Published
- 2025-03-11
- DOI
- https://doi.org/10.1002/chem.202403330
- Citations
- 1
- Primary Topic
- Chemical Synthesis and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Association Nationale de la Recherche et de la Technologie
- Centre National de la Recherche Scientifique
- Conseil Régional Aquitaine