Binding properties of human telomeric quadruplex multimers: A new route for drug design

Cummaro, Annunziata; Fotticchia, Iolanda; Franceschin, Marco; Giancola, Concetta; Petraccone, Luigi

doi:10.1016/j.biochi.2011.04.005

Cited by 70 publications

(50 citation statements)

References 46 publications

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“…Nevertheless, the high number of GGGTTA repeats makes the human telomeric G-strand potentially apt to fold into contiguous (or tandem) G4s, formed by the 21mer sequence (GGGTTA) 3 GGG and connected by TTA linkers, in particular at the 3 0 -overhangs (200 nucleotide average length [24,25]). Contiguous G4s are attractive structures for the design of telomere specific small ligands, with the ability to discriminate between isolated single G4s and contiguous G4s [26,27]. Do long telomeric strands actually fold into contiguous G4s?…”

Section: Introductionmentioning

confidence: 99%

Understanding the stability of DNA G-quadruplex units in long human telomeric strands

Bugaut

Alberti

2015

Biochimie

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Human telomeric DNA is composed of GGGTTA repeats. The presence of consecutive guanines makes the telomeric G-strand prone to fold into contiguous (or tandem) G-quadruplexes (G4s). The aim of this study was to provide a clarified picture of the stability of telomeric tandem G4 structures as a function of the number of G4 units and of boundary sequences, and an understanding of the diversity of their melting behaviors in terms of the single G4 units composing them. To this purpose we undertook an UV-spectroscopic investigation of the structure and stability of telomeric repeats potentially able to fold into up to four contiguous G4s, flanked or not by TTA sequences at their 5' and 3' extremities. We explain why the stability of (GGGTTA)4m-1GGG structures (m = 2, 3, 4 …) decreases with increasing the number m of G4 units, whereas the stability of TTA-(GGGTTA)4m-1GGG-TTA structures does not. Our results support that the inner G4 units have similar stabilities, whereas the stabilities of the terminal G4 units are modulated by their flanking nucleotides: in a TTA-(GGGTTA)4m-1GGG-TTA tandem context, the terminal G4 units are roughly as stable as the inner G4 units; while in a (GGGTTA)4m-1GGG tandem context, the G4 at the 5' extremity is more stable than the G4 at the 3' extremity, which in turn is more stable than an inner G4. Our study provides new information about the global and local stability of telomeric tandem G4 structures under near physiological conditions.

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Section: Introductionmentioning

confidence: 99%

Understanding the stability of DNA G-quadruplex units in long human telomeric strands

Bugaut

Alberti

2015

Biochimie

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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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“…The binding curves were obtained by plotting the change in fluorescence intensity versus the G-quadruplex concentration. For the derivation of the binding constant, the binding curves were fitted to the following equation [37][38][39]:…”

Section: Absorption and Emission Spectramentioning

confidence: 99%

Interactions of ruthenium complexes containing indoloquinoline moiety with human telomeric G-quadruplex DNA

Yu¹,

Yu²,

Hao³

et al. 2014

Spectrochimica Acta Part A: Molecular and Biomolecular Spectros

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Binding properties of human telomeric quadruplex multimers: A new route for drug design

Cited by 70 publications

References 46 publications

Understanding the stability of DNA G-quadruplex units in long human telomeric strands

Understanding the stability of DNA G-quadruplex units in long human telomeric strands

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

Interactions of ruthenium complexes containing indoloquinoline moiety with human telomeric G-quadruplex DNA

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