Thioether Analogues of Disulfide‐Bridged Cyclic Peptides Targeting Death Receptor 5: Conformational Analysis,Dimerisation and Consequences for Receptor Activation |
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| Authors: | Dr. Karolina Pulka‐Ziach Dr. Valeria Pavet Neila Chekkat Dr. Karine Estieu‐Gionnet Roman Rohac Dr. Marie‐Charlotte Lechner Dr. Cristian R. Smulski Dr. Gabrielle Zeder‐Lutz Dr. Danièle Altschuh Dr. Hinrich Gronemeyer Prof. Dr. Sylvie Fournel Dr. Benoit Odaert Dr. Gilles Guichard |
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| Affiliation: | 1. Université de Bordeaux, CNRS, Institut Polytechnique de Bordeaux, UMR5248 CBMN, Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, 33607 Pessac (France);2. Present address: Faculty of Chemistry, University of Warsaw, Pasteura 1, 02‐093 Warsaw (Poland);3. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Equipe Labellisée Ligue Contre le Cancer, Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, University of Strasbourg, 1 rue Laurent Fries, 67404 Illkirch (France);4. UMR 7199 CNRS‐Université de Strasbourg, Faculté de Pharmacie, 74 Route du Rhin, B.?P. 60024, 67401 Illkirch Cédex (France);5. CNRS, Institut de Biologie Moléculaire et Cellulaire, Laboratoire d'Immunopathologie et Chimie Thérapeutique, 15 rue René Descartes, 67084 Strasbourg (France);6. Present address: University Medical Center Freiburg, CCI, Engesserstrasse 4, 79110 Freiburg (Germany);7. Biotechnologie et Signalisation Cellulaire, Université de Strasbourg, CNRS, ESBS, 300, Boulevard Sébastien Brant BP10413, 67412 Illkirch (France);8. Université de Bordeaux, CNRS, Institut Polytechnique de Bordeaux, UMR 5248 CBMN, All. Geoffroy Saint‐Hilaire, 33600 Pessac (France) |
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| Abstract: | 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. |
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| Keywords: | antitumor agents cyclization death receptors disulfide lanthionine peptides |
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