G-quadruplex ligands: Mechanisms of anticancer action and target binding

Il'inskiĭ, N S; Varizhuk, Anna M.; Бениаминов, А. Д.; Puzanov, M A; Shchelkina, A. K.; Kaliuzhnyĭ, D N

doi:10.1134/s0026893314060077

Cited by 23 publications

(16 citation statements)

References 106 publications

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“…[17][18][19][20][21][22] Due to their regulatory function in pathological processes, G-quadruplexes have been identified as interesting drug targets in anticancer research. [23][24][25] Many small molecules [26] and metal complexes, [27] most of them possessing flat psurfaces and positive charges, were found to bind and stabilize the folded secondary structure, thereby acting as potential anticancer drugs. [28] One well-known G-quadruplex binder is the natural product telomestatin, [29,30] which is a potent telomerase inhibitor due to its strong interaction with unimolecular G-quadruplexes found in the human telomeric sequence.…”

Section: Introductionmentioning

confidence: 99%

Precise Distance Measurements in DNA G‐Quadruplex Dimers and Sandwich Complexes by Pulsed Dipolar EPR Spectroscopy

et al. 2020

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DNA G-quadruplexes show a pronounced tendency to form higher-order structures, such as p-stacked dimers and aggregates with aromatic binding partners. Reliable methods for determining the structure of these non-covalent adducts are scarce. Here, we use artificial square-planar Cu(pyridine) 4 complexes, covalently incorporated into tetramolecular Gquadruplexes, as rigid spin labels for detecting dimeric structures and measuring intermolecular Cu 2+-Cu 2+ distances via pulsed dipolar EPR spectroscopy. A series of G-quadruplex dimers of different spatial dimensions, formed in tail-totail or head-to-head stacking mode, were unambiguously distinguished. Measured distances are in full agreement with results of molecular dynamics simulations. Furthermore, intercalation of two well-known G-quadruplex binders, PIPER and telomestatin, into G-quadruplex dimers resulting in sandwich complexes was investigated, and previously unknown binding modes were discovered. Additionally, we present evidence that free G-tetrads also intercalate into dimers. Our transition metal labeling approach, combined with pulsed EPR spectroscopy, opens new possibilities for examining structures of non-covalent DNA aggregates.

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Section: Introductionmentioning

confidence: 99%

Precise Distance Measurements in DNA G‐Quadruplex Dimers and Sandwich Complexes by Pulsed Dipolar EPR Spectroscopy

et al. 2020

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“…Chemical structures and associated activity data for approximately one thousand ligands are currently curated in the online G4 ligand database, and new chemotypes are frequently reported . Progress towards the goal of G4‐targeted therapy is frequently documented and it is not our intention to cover general G4 ligand design principles in this review, since they are covered comprehensively elsewhere , , . However, over the course of our endeavors in G4 ligand chemistry we have become more deeply interested in the potential of ligands to do more than simply bind G4 with the aim of enhancing their stability or extending their lifetime in vivo.…”

Section: Introductionmentioning

confidence: 99%

Binding and Beyond: What Else Can G‐Quadruplex Ligands Do?

2019

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G‐quadruplexes (G4) are four‐stranded structures formed from guanine‐rich oligonucleotides. Their defined 3D structures and polymorphic nature set them apart from classical nucleic acid morphology and suggest a range of potential applications in the development of functional materials. Meanwhile, the occurrence of G4 across the genomes of animals, plants and pathogens suggests roles for these structures in biology that may be exploited for therapeutic effect. Hundreds of G4 ligands are reported to bind these sequences with high specificity and affinity, but such ligands can also be engineered to do more than simply associate with G4 in a straightforward host‐guest fashion. Ligands have been developed that can switch G4 topology, direct the selective covalent modification of nucleic acid structures, or respond to external stimuli to permit spatiotemporal control of their activity. Herein we survey the main themes of such “value‐added” G4 ligands and consider the opportunities and challenges of their potential applications.

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“…Amongst the myriad of small molecule G4-binding ligands that have been synthesized one can find examples of ligands binding grooves, loop sequences, and tetrad faces of G4s. In some cases, binding of these ligands has been shown to stabilize, destabilize, and even alter the conformation of the G4 [ 5 – 7 ]. It would not be unreasonable to hypothesize that as our knowledge of protein-G4 interactions increases we will have examples of proteins that do the same.…”

Section: Introductionmentioning

confidence: 99%

On Characterizing the Interactions between Proteins and Guanine Quadruplex Structures of Nucleic Acids

McRae

Booy

Padilla-Meier

et al. 2017

Journal of Nucleic Acids

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Guanine quadruplexes (G4s) are four-stranded secondary structures of nucleic acids which are stabilized by noncanonical hydrogen bonding systems between the nitrogenous bases as well as extensive base stacking, or pi-pi, interactions. Formation of these structures in either genomic DNA or cellular RNA has the potential to affect cell biology in many facets including telomere maintenance, transcription, alternate splicing, and translation. Consequently, G4s have become therapeutic targets and several small molecule compounds have been developed which can bind such structures, yet little is known about how G4s interact with their native protein binding partners. This review focuses on the recognition of G4s by proteins and small peptides, comparing the modes of recognition that have thus far been observed. Emphasis will be placed on the information that has been gained through high-resolution crystallographic and NMR structures of G4/peptide complexes as well as biochemical investigations of binding specificity. By understanding the molecular features that lead to specificity of G4 binding by native proteins, we will be better equipped to target protein/G4 interactions for therapeutic purposes.

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G-quadruplex ligands: Mechanisms of anticancer action and target binding

Cited by 23 publications

References 106 publications

Precise Distance Measurements in DNA G‐Quadruplex Dimers and Sandwich Complexes by Pulsed Dipolar EPR Spectroscopy

Precise Distance Measurements in DNA G‐Quadruplex Dimers and Sandwich Complexes by Pulsed Dipolar EPR Spectroscopy

Binding and Beyond: What Else Can G‐Quadruplex Ligands Do?

On Characterizing the Interactions between Proteins and Guanine Quadruplex Structures of Nucleic Acids

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