Department of Food, Environmental and Nutritional Sciences (DEFENS), University of Milan (Università Degli Studi Di Milano), Milan, Italy.
Scientia Advice di Roberto Artali, 20832, Desio, MB, Italy.
Sci Rep. 2021 Feb 16;11(1):3869. doi: 10.1038/s41598-021-83474-9.
Poly ADP-ribose polymerases (PARP) are key proteins involved in DNA repair, maintenance as well as regulation of programmed cell death. For this reason they are important therapeutic targets for cancer treatment. Recent studies have revealed a close interplay between PARP1 recruitment and G-quadruplex stabilization, showing that PARP enzymes are activated upon treatment with a G4 ligand. In this work the DNA binding properties of a PARP-1 inhibitor derived from 7-azaindole-1-carboxamide, (2-[6-(4-pyrrolidin-1-ylmethyl-phenyl)-pyrrolo[2,3-b]pyridin-1-yl]-acetamide, compound 1) with model duplex and quadruplex DNA oligomers were studied by NMR, CD, fluorescence and molecular modelling. We provide evidence that compound 1 is a strong G-quadruplex binder. In addition we provide molecular details of the interaction of compound 1 with two model G-quadruplex structures: the single repeat of human telomeres, d(TTAGGGT), and the c-MYC promoter Pu22 sequence. The formation of defined and strong complexes with G-quadruplex models suggests a dual G4 stabilization/PARP inhibition mechanism of action for compound 1 and provides the molecular bases of its therapeutic potential.
聚 ADP-核糖聚合酶（PARP）是参与 DNA 修复、维持以及程序性细胞死亡调控的关键蛋白。因此，它们是癌症治疗的重要治疗靶点。最近的研究揭示了 PARP1 募集和 G-四链体稳定之间的密切相互作用，表明 PARP 酶在 G4 配体处理后被激活。在这项工作中，通过 NMR、CD、荧光和分子建模研究了源自 7-氮杂吲哚-1-甲酰胺的 PARP-1 抑制剂（2-[6-（4-吡咯烷-1-基甲基-苯基）-吡咯并[2,3-b]吡啶-1-基]-乙酰胺，化合物 1）与模型双链体和四链体 DNA 寡聚物的 DNA 结合特性。我们提供的证据表明，化合物 1 是一种强 G-四链体结合物。此外，我们还提供了化合物 1 与两种模型 G-四链体结构（人类端粒的单重复 d（TTAGGGGT）和 c-MYC 启动子 Pu22 序列）相互作用的分子细节。与 G-四链体模型形成明确且强的复合物表明化合物 1 具有双重 G4 稳定/PARP 抑制作用机制，并为其治疗潜力提供了分子基础。
