Reversible photoregulation of G-quadruplex DNA structures by non-covalent azobenzene derivatives

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Perrin, Auriane | Nay, Bastien | Hache, François | Changenet-Barret,, Pascale

Edité par CCSD -

International audience. G-quadruplexes (G4) are non-canonical DNA structures involved in important cell regulatory functions associated with their folding mechanism. The design of small ligands capable of modulating their formation/stabilization is therefore of growing interest for the development of new anti-cancer therapies. In particular, the reversible control of G4s using bistable photoswitches offers promising perspectives for applications in photopharmacology and DNA nanotechnology, but remains largely unexploited [1]. It has long been demonstrated that the folding/unfolding of human telomeric (HT) G4 sequences can be induced by azobenzene-derived photoswitches [2]. However, the dynamics and mechanisms underlying these processes have never been investigated. Here we present a comprehensive study of complexes made of non-covalent azobenzenes bearing quaternary ammonium substituents (AZO) with different G4 sequences, by using a combination of stationary and time-resolved optical and chiroptical spectroscopic methods. This study revealed a non-cooperative binding mode of AZO with HT G4 sequences of the type 5'-GGG(TTAGGG)3-3' and the thrombin-binding aptamer G4 sequence, 5'-GGTTGGTGTGGTTGG-3' (TBA), in the absence of physiological cations. The binding of AZO to DNA induces the formation of parallel G4 topologies that can be reversibly unfolded under UV/visible excitation without noticeable fatigue. Femtosecond transient absorption measurements show that the isomerization of AZO is slowed by a factor of 4 in the presence of G4 (62ps vs. 16ps), while millisecond time-resolved circular dichroism provides evidence that G4 unfolding takes place within a few tens of milliseconds [3].

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