Multimeric peptidomimetic architectures as Tools to Investigate activation of cell-surface receptors
We are interested to develop Synthetic Multivalent Ligands (SMLs) as tunable probes to modulate biological processes and to dissect signalling pathways associated with cell-surface receptors. Ligand-induced oligomerization is an important process for activating cell surface receptors such as tumor necrosis factor (TNF) receptor superfamilies., In
collaboration with S. Fournel (IBMC, Strasbourg), H Gronemeyer (IGBMC, Illkirch), O. Micheau (INSERM U866, Dijon),we have been focusing on the design of trimeric ligands targeting CD40 and TRAIL-R2, two TNFRs playing a major role in immunity and apoptosis, respectively. Early work led to the design of C3-symmetric peptides constructed on macrocyclic plateforms (e.g. cyclic D,Lhexapeptides, cyclic β-peptides) that were shown to mimic at least partially the biological effects of CD40L (activation of dendritic cells,…). We recently extended this approach to a new series of synthetic multimeric molecules incorporating peptide sequences reported to bind TRAIL-R2. Covalent dimeric and trimeric versions were found to bind TRAIL-R2 with increased avidity compared to monomers and more importantly, to selectively trigger the TRAIL apoptotic pathway in various cancer cell lines.
Figure : Multivalent display as a strategy to activate TNFRs.Exemples of trimeric platform investigated.
Selected Publications : Pavet et al. Cancer Res. 2010, 70, 1101-1110 ; Trouche et al. J. Am. Chem. Soc. 2007, 129,13480-92 ; Bianco et al. Org. Biol. Chem. 2006, 4, 1461-1463; Fournel et al. Nature Chem. Biol. 2005, 1, 377-382.