Targeting Human Telomeric Higher-Order DNA: Dimeric G-Quadruplex Units Serve as Preferred Binding Site

Zhao, Chuanqi; Wu, Li; Ren, Jinsong; Xu, Yan; Qu, Xiaogang

doi:10.1021/ja410723r

Cited by 124 publications

(116 citation statements)

References 60 publications

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“…In these sequences, however, only the telomeric sequence has the ability to form multimeric G-quadruplexes. That is to say, the ligands that can interact specifically with telomeric multimeric G-quadruplexes could be developed as promising anticancer drugs with few side effects related to other potential G-quadruplex-forming regions (35,38). …”

Section: Introductionmentioning

confidence: 99%

Two cationic porphyrin isomers showing different multimeric G-quadruplex recognition specificity against monomeric G-quadruplexes

Huang

Zhu

et al. 2014

Nucleic Acids Res

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Ligands that can interact specifically with telomeric multimeric G-quadruplexes could be developed as promising anticancer drugs with few side effects related to other G-quadruplex-forming regions. In this paper, a new cationic porphyrin derivative, m-TMPipEOPP, was synthesized and characterized. Its multimeric G-quadruplex recognition specificity under molecular crowding conditions was compared to its isomer p-TMPipEOPP. The slight structural difference accounts for different multimeric G-quadruplex recognition specificity for the two isomers. p-TMPipEOPP can barely discriminate between multimeric and monomeric G-quadruplexes. By contrast, m-TMPipEOPP can bind with multimeric but not with monomeric G-quadruplexes. p-TMPipEOPP might bind to multimeric G-quadruplexes by two modes: sandwich-like end-stacking mode and pocket-dependent intercalative mode. Increasing the pocket size between adjacent two G-quadruplex uints is beneficial for the latter mode. m-TMPipEOPP might bind to multimeric G-quadruplexes by a side binding mode, which confers m-TMPipEOPP with higher multimeric G-quadruplex recognition specificity compared to p-TMPipEOPP. m-TMPipEOPP increases the stability of multimeric G-quadruplex under both dilute and molecular crowding conditions but its G-quadruplex-stabilizing ability is a little weaker than p-TMPipEOPP. These results provide important information for the design of highly specific multimeric G-quadruplex ligands. Another interesting finding is that pocket size is an important factor in determining the stability of multimeric G-quadruplexes.

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Section: Introductionmentioning

confidence: 99%

Two cationic porphyrin isomers showing different multimeric G-quadruplex recognition specificity against monomeric G-quadruplexes

Huang

Zhu

et al. 2014

Nucleic Acids Res

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“…[7][8][9] Thus, structural information of the non-B DNA structures present in the 3' telomeric overhang is vital for designing highly specific cancer therapeutic agents as the presence of much debated higher order structures can be a novel target. [10][11][12] Most of current studies are focused on telomeric DNA with four TTAGGG repeats that can only host one G-quadruplex unit. The simplicity of the system has enabled higher resolution structural information on telomeric G-quadruplexes by NMR or X-ray techniques.…”

Section: Introductionmentioning

confidence: 99%

Interaction of G-Quadruplexes in the Full-Length 3′ Human Telomeric Overhang

et al. 2014

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The 3' human telomeric overhang provides ample opportunities for the formation and interaction of G-quadruplexes, which have shown impacts on many biological functions including telomerase activities in the telomere region. However, in the few investigations on DNA constructs that approach to the full length of the human telomeric overhang, the presence of higher-order quadruplex-quadruplex interactions is still a subject of debate. Herein, we employed dynamic splint ligation (DSL) to prepare a DNA construct, 5'-(TTAGGG)24 or 24G, which has the length comparable to the full stretch of 3' human telomeric overhang. Using mechanical unfolding assays in laser tweezers, we observed a minor population (∼5%) of higher-order interactions between G-quadruplexes, while the majority of the quadruplexes follow the bead-on-a-string model. Analyses on the noninteracting G-quadruplexes in the 24G construct showed features similar to those of the stand-alone G-quadruplexes in the 5'-(TTAGGG)4 (4G) construct. As each 24G construct contains as many as six G-quadruplexes, this method offers increased throughput for the time-consuming mechanical unfolding experiments of non-B DNA structures.

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“…Furthermore, it should also be noted that complexes 2 c and 1 exhibited higher than or comparable affinities/thermal stabilization than other G2T1 binders previously reported in the literature (Table S2 in the Supporting Information) 24, 26, 27, 29, 30, 31…”

Section: Resultsmentioning

confidence: 50%

“…Though a large number of small molecules have been previously developed as single G‐quadruplex DNA binders,5, 6, 7, 8, 9 comparatively very few have been studied (or indeed specifically designed) as binders for multimeric G‐quadruplex structures 24, 25, 26, 27, 28, 29, 30, 31, 32. This includes a chiral cyclic helicene proposed to bind in the cleft between two human telomeric G‐quadruplexes linked by a TTA spacer 25.…”

Section: Introductionmentioning

confidence: 99%

Dinickel–Salphen Complexes as Binders of Human Telomeric Dimeric G‐Quadruplexes

Zhou

Liao

et al. 2017

Chemistry A European J

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Three new polyether‐tethered dinickel–salphen complexes (2 a–c) have been synthesized and fully characterized by NMR spectroscopy, mass spectrometry, and elemental analyses. The binding affinity and selectivity of these complexes and of the parent mono‐nickel complex (1) towards dimeric quadruplex DNA have been determined by UV/Vis titrations, fluorescence spectroscopy, CD spectroscopy, and electrophoresis. These studies have shown that the dinickel–salphen complex with the longest polyether linker (2 c) has higher binding affinity and selectivity towards dimeric quadruplexes (over monomeric quadruplexes) than the dinickel–salphen complexes with the shorter polyether linkers (2 a and 2 b). Complex 2 c also has higher selectivity towards human telomeric dimeric quadruplexes with one TTA linker than the monometallic complex 1. Based on the spectroscopic data, a possible binding mode between complex 2 c and the dimeric G‐quadruplex DNA under study is proposed.

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Targeting Human Telomeric Higher-Order DNA: Dimeric G-Quadruplex Units Serve as Preferred Binding Site

Cited by 124 publications

References 60 publications

Two cationic porphyrin isomers showing different multimeric G-quadruplex recognition specificity against monomeric G-quadruplexes

Two cationic porphyrin isomers showing different multimeric G-quadruplex recognition specificity against monomeric G-quadruplexes

Interaction of G-Quadruplexes in the Full-Length 3′ Human Telomeric Overhang

Dinickel–Salphen Complexes as Binders of Human Telomeric Dimeric G‐Quadruplexes

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