G-quadruplex structures in the human genome as novel therapeutic targets.
G-quadruplex structures in the human genome as novel therapeutic targets.
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DOI：
10.3390/molecules181012368
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发表时间：
2013-10-08
期刊：
影响因子：
--
通讯作者：
Folini M
中科院分区：
文献类型：
--
作者：
Bidzinska J;Cimino-Reale G;Zaffaroni N;Folini M
G-四链体是可在富含鸟嘌呤的核酸序列内形成的二级结构。端粒在这方面受到了广泛的关注，因为它们可以折叠成几个不同的分子内G-四链体，导致合理的设计和G-四链体稳定分子的发展。这些配体显示出在体外和体内肿瘤模型中选择性地发挥抗增殖和化学增敏活性，而不明显影响正常细胞。这些发现表明它们可能是临床应用的候选药物。除了在端粒中，G-四链体可以在人类基因组中的其他位置形成，包括基因启动子和非翻译区。例如，MYC、KIT或KRAS启动子内G-四链体结构的稳定化导致基因报告基因测定或选定实验模型中相应癌基因的下调。此外，通过稳定位于前mRNA内的G-四链体，可以影响许多基因的选择性剪接以获得治疗益处。现在出现的是，G-四链体结构可能作为几个生物过程的关键调节器。因此，它们被认为是广谱抗癌疗法的有吸引力的靶标，并且正在努力开发具有改进的G-四链体识别特性的各种配体。Quarfloxin是一种氟喹诺酮衍生物，旨在靶向核糖体DNA内的G-四链体并破坏蛋白质-DNA相互作用，已进入不同恶性肿瘤的临床试验。这篇综述将提供一些提示G-四链体结构在生物过程中的作用，并将评估其作为新的治疗靶点的意义。
G-quadruplexes are secondary structures that may form within guanine-rich nucleic acid sequences. Telomeres have received much attention in this regard since they can fold into several distinct intramolecular G-quadruplexes, leading to the rational design and development of G-quadruplex-stabilizing molecules. These ligands were shown to selectively exert an antiproliferative and chemosensitizing activity in in vitro and in vivo tumor models, without appreciably affecting normal cells. Such findings point to them as possible drug candidates for clinical applications. Other than in telomeres, G-quadruplexes may form at additional locations in the human genome, including gene promoters and untranslated regions. For instance, stabilization of G-quadruplex structures within the promoter of MYC, KIT, or KRAS resulted in the down-regulation of the corresponding oncogene either in gene reporter assays or in selected experimental models. In addition, the alternative splicing of a number of genes may be affected for a therapeutic benefit through the stabilization of G-quadruplexes located within pre-mRNAs. It is now emerging that G-quadruplex structures may act as key regulators of several biological processes. Consequently, they are considered as attractive targets for broad-spectrum anticancer therapies, and much effort is being made to develop a variety of ligands with improved G-quadruplex recognition properties. Quarfloxin, a fluoroquinolone derivative designed to target a G-quadruplex within ribosomal DNA and disrupt protein-DNA interactions, has entered clinical trials for different malignancies. This review will provide some hints on the role of G-quadruplex structures in biological processes and will evaluate their implications as novel therapeutic targets.
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TrisubStttestated的异丙恶唑作为新的G四链体结合配体：C-KIT癌基因表达的小分子调节。
影响因子：
15
作者：
Bejugam, Mallesham;Sewitz, Sven;Shirude, Pravin S.;Rodriguez, Raphael;Shahid, Ramla;Balasubramanian, Shankar
通讯作者：
Balasubramanian, Shankar
DOI：
10.1038/nrg3296
发表时间：
2012-11
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
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影响因子：
14.9
作者：
Bugaut A;Balasubramanian S
通讯作者：
Balasubramanian S
影响因子：
8.8
作者：
Cairney CJ;Hoare SF;Daidone MG;Zaffaroni N;Keith WN
通讯作者：
Keith WN
影响因子：
7.3
作者：
Cogoi, Susanna;Paramasivam, Manikandan;Xodo, Luigi E.
通讯作者：
Xodo, Luigi E.