Kotras Clément, Fossépré Mathieu, Roger Maxime, Gervais Virginie, Richeter Sébastien, Gerbier Philippe, Ulrich Sébastien, Surin Mathieu, Clément Sébastien
ICGM Institut Charles Gerhardt Montpellier, UMR 5253, CNRS, Université de Montpellier, ENSCM, Montpellier, France.
Laboratory for Chemistry of Novel Materials, Center of Innovation and Research in Materials and Polymers, University of Mons-UMONS, Mons, Belgium.
Front Chem. 2019 Jul 11;7:493. doi: 10.3389/fchem.2019.00493. eCollection 2019.
Guanine-quadruplexes (G4s) are targets for anticancer therapeutics. In this context, human telomeric DNA (HT-DNA) that can fold into G4s sequences are of particular interest, and their stabilization with small molecules through a visualizable process has become a challenge. As a new type of ligand for HT-G4, we designed a tetraimidazolium tetraphenylethene () as a water-soluble light-up G4 probe. We study its G4-binding properties with HT-DNA by UV-Visible absorption, circular dichroism and fluorescence spectroscopies, which provide insights into the interactions between and G4-DNA. Remarkably, shows a strong fluorescence enhancement and large shifts upon binding to G4, which is valuable for detecting G4s. The association constants for the /G4 complex were evaluated in different solution conditions via isothermal titration calorimetry (ITC), and its binding modes were explored by molecular modeling showing a groove-binding mechanism. The stabilization of G4 by has been assessed by Fluorescence Resonance Energy Transfer (FRET) melting assays, which show a strong stabilization (Δ around +20°C), together with a specificity toward G4 with respect to double-stranded DNA.
鸟嘌呤四链体（G4s）是抗癌治疗的靶点。在这种情况下，能够折叠成G4序列的人类端粒DNA（HT-DNA）特别受关注，而通过可视化过程用小分子对其进行稳定化已成为一项挑战。作为一种新型的HT-G4配体，我们设计了一种四咪唑四苯乙烯（）作为水溶性发光G4探针。我们通过紫外可见吸收光谱、圆二色光谱和荧光光谱研究了它与HT-DNA的G4结合特性，这些研究为与G4-DNA之间的相互作用提供了见解。值得注意的是，与G4结合时显示出强烈的荧光增强和较大的光谱位移，这对于检测G4s很有价值。通过等温滴定量热法（ITC）在不同溶液条件下评估了与G4复合物的结合常数，并通过分子建模探索了其结合模式，结果显示为沟槽结合机制。通过荧光共振能量转移（FRET）熔解分析评估了对G4的稳定作用，结果显示出很强的稳定作用（Δ约为+20°C），并且相对于双链DNA对G4具有特异性。
