Thioether analogues of disulfide-bridged cyclic peptides targeting death receptor 5: conformational analysis, dimerisation and consequences for receptor activation.
Fiche publication
Date publication
janvier 2015
Journal
Chembiochem : a European journal of chemical biology
Auteurs
Membres identifiés du Cancéropôle Est :
Pr FOURNEL Sylvie, Dr GRONEMEYER Hinrich
Tous les auteurs :
Pulka-Ziach K, Pavet V, Chekkat N, Estieu-Gionnet K, Rohac R, Lechner MC, Smulski CR, Zeder-Lutz G, Altschuh D, Gronemeyer H, Fournel S, Odaert B, Guichard G
Lien Pubmed
Résumé
Cyclic peptides containing redox-stable thioether bridges might provide a useful alternative to disulfide-bridged bioactive peptides. We report the effect of replacing the disulfide bridge with a lanthionine linkage in a 16-mer cyclic peptide that binds to death receptor 5 (DR5, TRAIL-R2). Upon covalent oligomerisation, the disulfide-bridged peptide has previously shown similar behaviour to that of TNF-related apoptosis inducing ligand (TRAIL), by selectively triggering the DR5 cell death pathway. The structural and biological properties of the DR5-binding peptide and its desulfurised analogue were compared. Surface plasmon resonance (SPR) data suggest that these peptides bind DR5 with comparable affinities. The same holds true for dimeric versions of these peptides: the thioether is able to induce DR5-mediated apoptosis of BJAB lymphoma and tumorigenic BJELR cells, albeit to a slightly lower extent compared to its disulfide homologue. NMR analysis revealed subtle variation in the conformations of the two peptides and suggests that the thioether peptide is slightly less folded than its disulfide homologue. These observations could account for the different capability of the two dimers to cluster DR5 receptors on the cell surface and to trigger apoptosis. Nevertheless, our results suggest that the thioether peptide is a potential candidate for evaluation in animal models.
Mots clés
Alanine, analogs & derivatives, Antineoplastic Agents, chemistry, Apoptosis, drug effects, Chemistry Techniques, Synthetic, Dimerization, Disulfides, chemistry, Humans, Lymphoma, drug therapy, Magnetic Resonance Spectroscopy, Molecular Targeted Therapy, Peptides, Cyclic, chemistry, Protein Conformation, Receptors, TNF-Related Apoptosis-Inducing Ligand, metabolism, Sulfides, chemistry, Surface Plasmon Resonance
Référence
Chembiochem. 2015 Jan;16(2):293-301