Structure and Stability of Human Telomeric G-Quadruplex with Preclinical 9-Amino Acridines

Ruben Ferreira, Roberto Artali, Adam Benoit, Raimundo Gargallo, Ramon Eritja, David M. Ferguson, Yuk Y. Sham, Stefania Mazzini

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

G-quadruplexes are higher-order DNA structures formed from guanine-rich sequences, and have been identified as attractive anticancer drug targets. Elucidating the three-dimensional structure of G-quadruplex with 9-amino acridines and the specific interactions involved in binding selectivity are the key to understanding their mechanism of action. Fluorescence titration assays, competitive dialysis and NMR studies have been used to study the binding specificity of 9-amino acridines to DNA. Structural models of the complexes with the telomeric DNA G-quadruplex based on NMR measurements were developed and further examined by molecular dynamics simulations and free energy calculations. Selective binding of 9-amino acridines for G-quadruplex sequences were observed. These compounds bind between A and G-tetrads, involving significant π-π interactions and several strong hydrogen bonds. The specific interactions between different moieties of the 9-amino acridines to the DNA were examined and shown to play a significant role in governing the overall stabilities of DNA G-quadruplex complexes. Both 9-amino acridines, with similar binding affinities to the G-quadruplex, were shown to induce different level of structural stabilization through intercalation. This unique property of altering structural stability is likely a contributing factor for affecting telomerase function and, subsequently, the observed differences in the anticancer activities between the two 9-amino acridines.

Original languageEnglish (US)
Article numbere57701
JournalPloS one
Volume8
Issue number3
DOIs
StatePublished - Mar 15 2013

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acridines
G-Quadruplexes
Acridines
DNA
Nuclear magnetic resonance
telomerase
Dialysis
molecular dynamics
antineoplastic agents
Telomerase
Structural Models
guanine
Guanine
Molecular Dynamics Simulation
Intercalation
dialysis
titration
Titration
Free energy
hydrogen

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Ferreira, R., Artali, R., Benoit, A., Gargallo, R., Eritja, R., Ferguson, D. M., ... Mazzini, S. (2013). Structure and Stability of Human Telomeric G-Quadruplex with Preclinical 9-Amino Acridines. PloS one, 8(3), [e57701]. https://doi.org/10.1371/journal.pone.0057701

Structure and Stability of Human Telomeric G-Quadruplex with Preclinical 9-Amino Acridines. / Ferreira, Ruben; Artali, Roberto; Benoit, Adam; Gargallo, Raimundo; Eritja, Ramon; Ferguson, David M.; Sham, Yuk Y.; Mazzini, Stefania.

In: PloS one, Vol. 8, No. 3, e57701, 15.03.2013.

Research output: Contribution to journalArticle

Ferreira, Ruben ; Artali, Roberto ; Benoit, Adam ; Gargallo, Raimundo ; Eritja, Ramon ; Ferguson, David M. ; Sham, Yuk Y. ; Mazzini, Stefania. / Structure and Stability of Human Telomeric G-Quadruplex with Preclinical 9-Amino Acridines. In: PloS one. 2013 ; Vol. 8, No. 3.
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