Cell-Permeable Peptide Inhibitors of the p53-hDM2 Interaction via Foldamer Helix Mimicry and Bis-Thioether Stapling
Combining helical foldamers with α-peptides can produce α-helix mimetics with a reduced peptide character and enhanced resistance to proteolysis. Previously, we engineered a hybrid peptide-oligourea sequence replicating the N-terminal α-helical domain of p53 to achieve high affinity binding to hDM2. Here, we further advance this strategy by combining the foldamer approach with side chain cross-linking to create more constrained cell-permeable inhibitors capable of effectively engaging the target within cells. Starting from the crystal structure of the foldamer-hDM2 complex, we identified specific sites suitable for stapling, and generated a small library of macrocyclic foldamer-peptide hybrids. The most promising binders were subsequently optimized for cellular uptake and tested in a cellular assay. We observed that the introduction of a short segment of positively charged residues at the <i>N</i>-terminus of the sequence led to inhibitors that exhibited cytotoxic activity independently of p53. In contrast, neutral acetylated peptide-foldamer macrocycles demonstrated activity in a p53-dependent manner.
Authors
- Abdel‐Majid Khatib (ORCID: https://orcid.org/0000-0001-6957-0384)
- Emmanuelle Thinon (ORCID: https://orcid.org/0000-0001-9248-5655)
- François Hallé (ORCID: https://orcid.org/0000-0002-5324-8160)
- Sébastien R. Goudreau (ORCID: https://orcid.org/0000-0002-2803-876X)
- Maxime Neuville
- Morgane Pasco (ORCID: https://orcid.org/0000-0002-1556-2802)
- Gilles Guichard (ORCID: https://orcid.org/0000-0002-2584-7502)
- 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)
- Sichuan University (CN)
- Bordeaux Population Health (FR)
- Chengdu University (CN)
- Chimie et Biologie des Membranes et des Nanoobjects (FR)
- Institut de Chimie Organique et Analytique (FR)
- Institut Européen de Chimie et Biologie (FR)
- Institut Polytechnique de Bordeaux (FR)
- BoRdeaux Institute of onCology (FR)
- Rockefeller University (US)
- South China University of Technology (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-12-25
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01762
- Citations
- 7
- Primary Topic
- Chemical Synthesis and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 1.64
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
- Université de Bordeaux
- Conseil Régional Aquitaine