title: Structure and stability of human telomeric G-quadruplex with preclinical 9-amino acridines.
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.
authors.affiliation: Institute for Research in Biomedicine, IQAC-CSIC, CIBER-BBN Networking Center on Bioengineering, Biomaterials and Nanomedicine, Barcelona, Spain.
authors.forename: Ruben
authors.initials: R
authors.lastname: Ferreira
authors.forename: Roberto
authors.initials: R
authors.lastname: Artali
authors.forename: Adam
authors.initials: A
authors.lastname: Benoit
authors.forename: Raimundo
authors.initials: R
authors.lastname: Gargallo
authors.forename: Ramon
authors.initials: R
authors.lastname: Eritja
authors.forename: David M
authors.initials: DM
authors.lastname: Ferguson
authors.forename: Yuk Y
authors.initials: YY
authors.lastname: Sham
authors.forename: Stefania
authors.initials: S
authors.lastname: Mazzini
mesh_terms: D000609:Aminoacridines / Q000737:chemistry* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use; D004273:DNA, Neoplasm / Q000737:chemistry*; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000737:chemistry / Q000188:drug therapy; D016615:Telomere / Q000737:chemistry*
chemical_list: D000609:Aminoacridines; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm
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