Structural Basis for Telomeric G-Quadruplex Targeting by Naphthalene Diimide Ligands
Structural Basis for Telomeric G-Quadruplex Targeting by Naphthalene Diimide Ligands
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DOI：
10.1021/ja2102423
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发表时间：
2012-02-08
影响因子：
15
通讯作者：
Parkinson, Gary N.
中科院分区：
文献类型：
--
作者：
Collie, Gavin W.;Promontorio, Rossella;Parkinson, Gary N.
人类端粒的单链3‘端折叠成G-四链排列，抑制了悬垂与端粒酶的RNA模板杂交，并阻止了端粒在癌细胞中的维持。通过开发选择性小分子化合物来热稳定四链G-四链结构的人端粒DNA的能力是调节端粒酶活性从而选择性地抑制癌细胞生长的一条治疗途径。到目前为止，开发具有必要的选择性和亲和力的化合物来靶向平行链G-四链结构尤其具有挑战性，严重依赖于有限的结构数据。我们在这里报道了一种基于结构的方法来设计四链结合配体，以提高对人端粒DNA的亲和力和选择性。测定了22聚体分子内人端粒四聚体与两种有效的四取代萘二亚胺化合物之间的晶体结构，这些化合物带有带正电荷的N-甲基哌嗪侧链。这些化合物促进平行链四链拓扑结构，仅结合到每个四链链的3表面。在配体迁移率和与四链槽的相互作用方面，配合物之间存在着显著的差异。两个配体中的一个在晶体络合物中的活动性明显较小，更具四链稳定性，与四链磷酸基团形成多个静电/氢键接触。这里提供的数据为这一系列化合物的生物物理(对四链热稳定性的影响)和生物学数据(抑制癌细胞系的增殖和体内抗肿瘤活性的证据)提供了结构理论基础，从而为DNA四链结合小分子靶向端粒的概念提供了理论基础。
The folding of the single-stranded 3' end of the human telomere into G-quadruplex arrangements inhibits the overhang from hybridizing with the RNA template of telomerase and halts telomere maintenance in cancer cells. The ability to thermally stabilize human telomeric DNA as a four-stranded G-quadruplex structure by developing selective small molecule compounds is a therapeutic path to regulating telomerase activity and thereby selectively inhibit cancer cell growth. The development of compounds with the necessary selectivity and affinity to target parallel-stranded G-quadruplex structures has proved particularly challenging to date, relying heavily upon limited structural data. We report here on a structure-based approach to the design of quadruplex-binding ligands to enhance affinity and selectivity for human telomeric DNA. Crystal structures have been determined of complexes between a 22-mer intramolecular human telomeric quadruplex and two potent tetra-substituted naphthalene diimide compounds, functionalized with positively charged N-methyl-piperazine side-chains. These compounds promote parallel-stranded quadruplex topology, binding exclusively to the 3 surface of each quadruplex. There are significant differences between the complexes in terms of ligand mobility and in the interactions with quadruplex grooves. One of the two ligands is markedly less mobile in the crystal complex and is more quadruplex-stabilizing, forming multiple electrostatic/hydrogen bond contacts with quadruplex phosphate groups. The data presented here provides a structural rationale for the biophysical (effects on quadruplex thermal stabilization) and biological data (inhibition of proliferation in cancer cell lines and evidence of in vivo antitumor activity) on compounds in this series and, thus, for the concept of telomere targeting with DNA quadruplex-binding small molecules.