Guanidinium‐Stapled Helical Peptides for Targeting Protein‐Protein Interactions
Peptide stapling has emerged as a versatile approach in drug discovery to reinforce secondary structure elements especially α-helices and improve properties of linear bioactive peptides. Inspired by the prevalence of arginine in protein-protein and protein-DNA interfaces, we investigated guanidinium-stapling as a means to constrain helical peptides. Guanidinium stapling was readily achieved on solid support, utilizing two orthogonally protected lysine or unatural α-amino acid residues with an amino function. This method allows for easy modulation of the nature and size of the staple as well as helix propensity. Evaluating a set of guanidinium-stapled peptides for their interaction with different protein targets identified several binders with increased target affinity. X-ray structure determination of four complexes revealed that all stapled peptides adopt a helical conformation upon protein binding. Notably, the disubstituted guanidinium generally exhibits a distinct cis/trans conformation and, in one instance, retains a conserved hydrogen bond with the protein surface. By identifying, for the first time, the guanidinium moiety as an effective helical peptide stapling group, this research significantly expands the repertoire of α-helix stapling techniques for the creation of useful protein mimics.
Authors
- Carole Peluso‐Iltis
- Maxime Neuville
- Camille Perdriau
- Natacha Rochel (ORCID: https://orcid.org/0000-0002-3573-5889)
- Katharina Zimmeter (ORCID: https://orcid.org/0009-0000-2289-8091)
- Morgane Pasco (ORCID: https://orcid.org/0000-0002-1556-2802)
- Gavin W. Collie (ORCID: https://orcid.org/0000-0002-0406-922X)
- Gilles Guichard (ORCID: https://orcid.org/0000-0002-2584-7502)
- Judit Ősz
- Brice Kauffmann (ORCID: https://orcid.org/0000-0002-2932-3255)
- Claire Saragaglia (ORCID: https://orcid.org/0000-0002-9686-8992)
- Anaïs Luton
Institutions
- AstraZeneca (United Kingdom) (GB)
- Centre National de la Recherche Scientifique (FR)
- Université de Bordeaux (FR)
- Inserm (FR)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- Institut de Chimie de Strasbourg (FR)
- AstraZeneca (Singapore) (SG)
- Chimie et Biologie des Membranes et des Nanoobjects (FR)
- Institut de Chimie Organique et Analytique (FR)
- Institut Européen de Chimie et Biologie (FR)
- Institut de Biologie Structurale (FR)
- AstraZeneca (Germany) (DE)
- Institut Polytechnique de Bordeaux (FR)
Publication Details
- Journal
- Angewandte Chemie International Edition
- Published
- 2024-12-23
- DOI
- https://doi.org/10.1002/anie.202416348
- Citations
- 11
- Primary Topic
- Chemical Synthesis and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 2.57
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