Fiche publication
Date publication
décembre 2024
Journal
Angewandte Chemie (International ed. in English)
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ROCHEL-GUIBERTEAU Natacha
,
Dr OSZ-PAPAI Judit
Tous les auteurs :
Perdriau C, Luton A, Zimmeter K, Neuville M, Saragaglia C, Peluso-Iltis C, Osz J, Kauffmann B, Collie GW, Rochel N, Guichard G, Pasco M
Lien Pubmed
Résumé
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.
Mots clés
Guanidinium, Helix, Protein-protein interaction, Stapled peptide, solid-phase synthesis
Référence
Angew Chem Int Ed Engl. 2024 12 23;:e202416348
