Rocca Roberta, Scionti Francesca, Nadai Matteo, Moraca Federica, Maruca Annalisa, Costa Giosuè, Catalano Raffaella, Juli Giada, Di Martino Maria Teresa, Ortuso Francesco, Alcaro Stefano, Tagliaferri Pierosandro, Tassone Pierfrancesco, Richter Sara N, Artese Anna
Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Campus "Salvatore Venuta", Viale Europa, 88100 Catanzaro, Italy.
Net4science Srl, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy.
Pharmaceuticals (Basel). 2022 Apr 28;15(5):548. doi: 10.3390/ph15050548.
In mammalian cells, telomerase transcribes telomeres in large G-rich non-coding RNA, known as telomeric repeat-containing RNA (TERRA), which folds into noncanonical nucleic acid secondary structures called G-quadruplexes (G4s). Since TERRA G4 has been shown to be involved in telomere length and translation regulation, it could provide valuable insight into fundamental biological processes, such as cancer growth, and TERRA G4 binders could represent an innovative strategy for cancer treatment. In this work, the three best candidates identified in our previous virtual screening campaign on bimolecular DNA/RNA G4s were investigated on the monomolecular Tel DNA and TERRA G4s by means of molecular modelling simulations and in vitro and in cell analysis. The results obtained in this work highlighted the stabilizing power of all the three candidates on TERRA G4. In particular, the two compounds characterized by a chromene scaffold were selective TERRA G4 binders, while the compound with a naphthyridine core acted as a dual Tel/TERRA G4-binder. A biophysical investigation by circular dichroism confirmed the relative stabilization efficiency of the compounds towards TERRA and Tel G4s. The TERRA G4 stabilizing showed good antiproliferative activity against colorectal and lung adenocarcinoma cell lines. Lead optimization to increase TERRA G4 stabilization may provide new powerful tools against cancer.
在哺乳动物细胞中，端粒酶转录富含鸟嘌呤的大型非编码RNA中的端粒，这种RNA被称为含端粒重复序列的RNA（TERRA），它折叠成称为G-四链体（G4s）的非经典核酸二级结构。由于TERRA G4已被证明参与端粒长度和翻译调控，它可以为癌症生长等基本生物学过程提供有价值的见解，并且TERRA G4结合剂可能代表一种创新的癌症治疗策略。在这项工作中，通过分子模拟以及体外和细胞分析，对我们之前针对双分子DNA/RNA G4s的虚拟筛选活动中确定的三个最佳候选物在单分子端粒DNA和TERRA G4s上进行了研究。这项工作获得的结果突出了所有三个候选物对TERRA G4的稳定作用。特别是，两种具有色烯支架的化合物是选择性TERRA G4结合剂，而具有萘啶核心的化合物则作为端粒/TERRA G4双结合剂。通过圆二色性进行的生物物理研究证实了这些化合物对TERRA和端粒G4s的相对稳定效率。TERRA G4稳定剂对结肠直肠癌和肺腺癌细胞系显示出良好的抗增殖活性。通过先导化合物优化来提高TERRA G4的稳定性可能会提供对抗癌症的新的有力工具。
