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G-quadruplexes in Cancer Research: from Targets to Nanotools?

Dr. Alessio Terenzi
Donostia International Physics Center
Friday, 15 February 2019 12:00

G-quadruplexes (G4s) are highly polymorphic DNA/RNA motifs that assemble into non-canonical four-stranded helical structures.[1] They are thought to have key biological roles, such as in gene regulation. G4s are particularly enriched in many human cancer-related gene promoters, making them valuable targets for anticancer drugs.[2] In this context, we have recently reported on the promising DNA binding profiles of 4,4’-bipyridine-based dinuclear Pt(II) metallacyles.[3] Considering the promising results, we synthesized a Pt-based metallacycle designed to have an improved DNA-binding profile and favourable optical properties which allowed a thorough investigation of its fate inside cancer cells.

Interestingly, most of human G-rich domains form multiple adjacent G4 units within relatively long sequences. However, all thermodynamic and structural data reported to date, apply to single G4 units derived from short truncated sequences. The current design of G4-targeting molecules does not consider the interplay between neighbouring G4s, which could thwart these drug-discovery efforts. As a case study, we investigated the c-KIT promoter which contains a G-rich domain potentially able to form three adjacent G4s and we showed that these quadruplexes cannot be analysed independently, but they are indeed correlated to each other. G4s are becoming more and more popular not only as targets in cancer therapy, but also as tools in diverse disciplines such as nanotechnology[4] and nanoelectronics.[5] We propose to use multiple G4s to create nanotools with biomedical applications. Long ssDNA sequences containing ≥ eight adjacent G4 units will serve as a new tool for drug delivery. The plan is to develop a new system called G-NanoTrain in which the multiple G4 units act as separate carriages for protecting a cargo of anticancer drugs, which are selectively guided to cancer cells by an aptameric engine.

[1]          R. Hänsel-Hertsch, M. Di Antonio, S. Balasubramanian, Nat. Rev. Mol. Cell Biol. 2017, 18, 279–284.

[2]          S. Neidle, Nat. Rev. Chem. 2017, 1, 0041.

[3]          O. Domarco, D. Lötsch, J. Schreiber, C. Dinhof, S. Van Schoonhoven, M. D. García, C. Peinador, B. K. Keppler, W. Berger, A. Terenzi, Dalt. Trans. 2017, 46, 329–332.

[4]          L. A. Yatsunyk, O. Mendoza, J. L. Mergny, Acc. Chem. Res. 2014, 47, 1836–1844.

[5]          R.-R. Gao, T.-M. Yao, X.-Y. Lv, Y.-Y. Zhu, Y.-W. Zhang, S. Shi, Chem. Sci. 2017, 8, 4211–4222.