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人端粒G-四链体结构是指端粒末端富含鸟嘌呤(G)的DNA序列在一价阳离子(如K+和Na+)诱导下通过G碱基间Hoogsteen氢键连接形成的DNA二级结构。能够稳定端粒G-四链体的配体通常为端粒酶抑制剂,其可能成为抗肿瘤药物。应用CD,FRET,NMR光谱方法第一次较全面地研究了一种木脂素衍生物,紫玉兰素A(liliflorin A)与人端粒序列dGGG(TTAGGG)3G-四链体HTG21的相互作用,采用分子对接技术进一步研究紫玉兰素A与人端粒序列dTAGGG(TTAGGG)3G-四链体HTG23的结合位点。CD实验数据表明紫玉兰素A提高HTG21解链温度,FRET实验测得4.01μmol·L-紫玉兰素A可以将HTG21稳定温度提高3.2℃。NMR实验结果表明,加入紫玉兰素A三小时后HTG21核磁谱图出现明显变化。分子对接结果表明紫玉兰素A结合到HTG23较宽沟槽上,结合位点为G9,G10,G16和G17。紫玉兰素A是第一个能够选择性稳定人端粒G-四链体HTG21的木脂素类衍生物配体。实验结果为以人端粒G-四链体为靶点的抗肿瘤药物设计提供了新型候选化合物。
Human telomere G-quadruplex structure refers to the DNA secondary form of the DNA sequence formed by the terminal guanine-containing (G) DNA sequence that is connected by the Hoogsteen hydrogen bond between G bases under the induction of monovalent cations (eg, K + and Na + structure. Ligands that are capable of stabilizing the telomeric G-quadruplex are often telomerase inhibitors that may become antitumor drugs. For the first time, a lignan derivative, the interaction between liliflorin A and human telomere sequence dGGG (TTAGGG) 3G-quadruplex HTG21 was studied for the first time using CD, FRET and NMR spectroscopy. , The molecular docking technique was used to further study the binding sites of the granzyme A to telomere sequence dTAGGG (TTAGGG) 3G-quadruplex HTG23. The experimental data of CD indicate that the temperature of HTG21 is increased by the use of the granzyme A, and the temperature at which the HTG21 is stabilized by the FRET assay is 4.01 μmol·L-1. The results of NMR experiments showed that the nuclear magnetic resonance spectrum of HTG21 changed obviously after three hours. The molecular docking results indicated that the binding of granulysin A to the wider groove of HTG23 with binding sites G9, G10, G16 and G17. Magnolins A is the first lignan derivative ligand that selectively stabilizes human telomere G-quadruplex HTG21. The experimental results provide novel candidate compounds for the design of anticancer drugs targeting human telomere G-quadruplexes.