Department of Food, Environmental and Nutritional Sciences (DEFENS), University of Milan (Università degli Studi di Milano), 20133 Milan, Italy.
Center for Research in Biosciences & Health Technologies (CBIOS), Universidade Lusófona de Humanidades e Tecnologias, Campo Grande 376, 1749-024 Lisbon, Portugal.
Molecules. 2022 Jul 26;27(15):4792. doi: 10.3390/molecules27154792.
The enzyme PARP1 is an attractive target for cancer therapy, as it is involved in DNA repair processes. Several PARP1 inhibitors have been approved for clinical treatments. However, the rapid outbreak of resistance is seriously threatening the efficacy of these compounds, and alternative strategies are required to selectively regulate PARP1 activity. A noncanonical G-quadruplex-forming sequence within the PARP1 promoter was recently identified. In this study, we explore the interaction of known G-quadruplex binders with the G-quadruplex structure found in the PARP gene promoter region. The results obtained by NMR, CD, and fluorescence titration, also confirmed by molecular modeling studies, demonstrate a variety of different binding modes with small stabilization of the G-quadruplex sequence located at the PARP1 promoter. Surprisingly, only pyridostatin produces a strong stabilization of the G-quadruplex-forming sequence. This evidence makes the identification of a proper (3+1) stabilizing ligand a challenging goal for further investigation.
聚腺苷二磷酸核糖聚合酶 1（PARP1）是癌症治疗的一个有吸引力的靶点，因为它参与 DNA 修复过程。几种 PARP1 抑制剂已被批准用于临床治疗。然而，耐药性的迅速爆发严重威胁着这些化合物的疗效，需要寻找选择性调节 PARP1 活性的替代策略。最近在 PARP1 启动子中发现了一个非典型的 G-四链体形成序列。在这项研究中，我们探索了已知的 G-四链体结合物与 PARP 基因启动子区域中发现的 G-四链体结构的相互作用。NMR、CD 和荧光滴定的结果，也通过分子建模研究得到了证实，证明了与 PARP1 启动子处的 G-四链体序列存在多种不同的结合模式，并对其有一定的小程度稳定作用。令人惊讶的是，只有吡啶硫酮能够强烈稳定 G-四链体形成序列。这一证据表明，确定适当的（3+1）稳定配体是进一步研究的一个具有挑战性的目标。
