"Death Receptors (DR), members of the tumour necrosis factor (TNF) receptor family, have come into focus as suitable targets for the selective activation of the cell death (apoptosis) pathway in tumours in vivo without causing toxicity to healthy cells. Current approaches in clinical development for replicating the function of the TNF-related apoptosis inducing ligand (TRAIL) are restricted to recombinant proteins which have poor pharmacokinetic properties due to their susceptibility to proteolytic degradation, and high production cost. In this context, the identification of small molecules that can both bind to TRAIL receptors (eg. DR5) and activate the TRAIL pathway is of prime interest towards the development of new treatments complementary to conventional cancer therapy. The aim of this project is to develop foldamers (unnatural oligomers with predictable conformations) as proapoptotic DR ligands (e.g. TRAIL mimetics) by capitalizing on recent achievements of the host group in the fields of peptide and foldamer chemistry. The research plan involves the following specific objectives: 1) exploration of structural requirements for peptide-binding to DR5, 2) evaluation of foldameric systems for polyvalent display, 3) structure-guided design of DR5-binding helical foldamers and 4) construction and screening of focused foldamer libraries for binding to DRs. The applicant has experience in the synthesis of unnatural, constrained amino-acid synthesis for exploration of bioactive peptide conformations. She will join and bring her expertise to a host laboratory in France specialized in the synthesis and characterization of foldamers. Collaboration between the host and established European groups with prominent expertise in the biology of DRs and combinatorial chemistry has been organized. This project represents a significant leap forward in the application of peptidomimetic foldamers for the replication of protein-protein interactions and for the treatment of cancer."
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