Binding properties of human telomeric quadruplex multimers: A new route for drug design
Binding properties of human telomeric quadruplex multimers: A new route for drug design
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DOI：
10.1016/j.biochi.2011.04.005
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发表时间：
2011-09-01
期刊：
影响因子：
3.9
通讯作者：
Petraccone, Luigi
中科院分区：
文献类型：
--
作者：
Cummaro, Annunziata;Fotticchia, Iolanda;Petraccone, Luigi
人端粒G-四链体结构是一种有前途的抗癌治疗靶点。在过去的十年中，一些研究小组一直专注于设计新的配体，试图优化这些小分子和G-四链体基序之间的相互作用。在大多数这些研究中，靶结构是由短的人DNA端粒序列（通常21-26 nt）形成的单个四链体单元。然而，3 '末端单链人端粒DNA实际上是100-200个碱基长，并且可以通过聚集几个连续的四链体单元（多聚体）形成更高级的结构。尽管越来越多的关于较长的DNA端粒序列的结构信息，但是与较短的DNA端粒序列相比，关于这些序列的结合性质的数据非常少。（CD，UV和荧光）和量热技术（ITC）比较（TTAGGG）的结合特性（8）TT结构由两个相邻的四链体单元形成，具有（AG（3）TT）（4）单四链体结构的结合性质。使用三个侧链的三氮杂蒽衍生物azatrux和TMPyP 4阳离子卟啉作为四链体配体。我们发现，根据药物的不同，在多聚体结构中每个四链体单位的结合位点的数量小于或大于从单个四链体结合研究获得的结果的基础上预期的数量。这项工作表明，四链体单元沿着多聚体结构不表现为完全独立的。相邻四链体的存在导致从单个四链体结合研究中不可预测的不同结合能力。在全长端粒突出端中四链体四链体界面的存在可以在药物设计中提供有利因素，以增强对DNA端粒四链体的亲和力和选择性。(C)2011年Elsevier Masson SAS。All rights reserved.
Human telomeric G-quadruplex structures are known to be promising targets for an anticancer therapy. In the past decade, several research groups have been focused on the design of new ligands trying to optimize the interactions between these small molecules and the G-quadruplex motif. In most of these studies, the target structures were the single quadruplex units formed by short human DNA telomeric sequences (typically 21-26 nt). However, the 3'-terminal single-stranded human telomeric DNA is actually 100-200 bases long and can form higher-order structures by clustering several consecutive quadruplex units (multimers). Despite the increasing number of structural information on longer DNA telomeric sequences, very few data are available on the binding properties of these sequences compared with the shorter DNA telomeric sequences.In this paper we use a combination of spectroscopic (CD, UV and fluorescence) and calorimetric techniques (ITC) to compare the binding properties of the (TTAGGG)(8)TT structure formed by two adjacent quadruplex units with the binding properties of the (AG(3)TT)(4) single quadruplex structure. The three side-chained triazatruxene derivative azatrux and TMPyP4 cationic porphyrin were used as quadruplex ligands. We found that, depending on the drug, the number of binding sites per quadruplex unit available in the multimer structure was smaller or greater than the one expected on the basis of the results obtained from individual quadruplex binding studies. This work suggests that the quadruplex units along a multimer structure do not behave as completely independent. The presence of adjacent quadruplexes results in a diverse binding ability not predictable from single quadruplex binding studies. The existence of quadruplex quadruplex interfaces in the full length telomeric overhang may provide an advantageous factor in drug design to enhance both affinity and selectivity for DNA telomeric quadruplexes. (C) 2011 Elsevier Masson SAS. All rights reserved.