This proposal focuses on the formation of complex between DNA G-quadruplexes and a new family of synthetic ligands, which might be relevant for cancer therapy. The enzymatic acitivity of telomerase is critical to the immortality of most human cancer cell lines. However, telomeric DNA may fold into guanine quadruplex structures which are not competent substrates for telomerase. Therefore, the use of small molecule ligands to induce quadruplex stabilisation in telomeric DNA has potential as an anti-cancer strategy. A European collaboration recently engaged between I. Huc (Bordeaux, France) and S. Balasubramanian (Cambridge, UK) groups already led to the identification of a very promising compound, with exceptionnal potential for stabilising human G-quadruplex telomer. In addition a three dimensionnal helical compound (foldamer) has shown interesting activity. This project, involving chemistry, biology and biophysic, aims i) to systematically design and develop new analogues of this promising candidate, based on aromatic delta-peptide chemistry; ii) to evaluate their G-quadruplex binding affinity in telomere and others systems; iii) to establish structure-activity relationships; iv) to determine the key elements necessary for specific G-quadruplex recognition by solving the structure of the first ligand complexed with G-quadruplex. This original interdisciplinary proposal involves two international leading groups in their respective field, to develop new tools and knowledge on the growing interest on natural G-quadruplexes as new target for anti-cancer strategy. The applicant will have a crucial role in the development of this collaboration and will become an active and efficient third partner, when returning back to China at the end of the fellowship.
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