G-Quadruplex DNA as a Target for Drug Design

Kerwin, Sean M.

doi:10.2174/1381612003400849

Cited by 226 publications

(114 citation statements)

References 181 publications

(270 reference statements)

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“…Therefore, ligands that selectively bind to G-quadruplex structures may interfere with telomere structure and telomere elongation and replication of cancer cells [14,15]. Several reviews concerning telomerase inhibitors in general or quadruplex-based telomerase inhibitors have been published in the last few years [16][17][18][19][20][21][22][23]. The recent discovery of natural compounds such as cryptolepine [24] and telomestatin [25,26] or of synthetic pentacyclic acridines (such as RHPS4) [27] that interact with G-quartets led us to test the binding of ascididemin and meridine to G-quadruplexes.…”

Section: (B) a G-quartet (Left) And A Schematic Drawing Of An Intramentioning

confidence: 99%

Ascididemin and meridine stabilise G-quadruplexes and inhibit telomerase in vitro

Guittat

Cian

Rosu

et al. 2005

Biochimica et Biophysica Acta (BBA) - General Subjects

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Ascididemin and Meridine are two marine compounds with pyridoacridine skeletons known to exhibit interesting antitumour activities. These molecules have been reported to behave like DNA intercalators. In this study, dialysis competition assay and mass spectrometry experiments were used to determine the affinity of ascididemin and meridine for DNA structures among duplexes, triplexes, quadruplexes and single-strands. Our data confirm that ascididemin and meridine interact with DNA but also recognize triplex and quadruplex structures. These molecules exhibit a significant preference for quadruplexes over duplexes or single-strands. Meridine is a stronger quadruplex ligand and therefore a stronger telomerase inhibitor than ascididemin (IC 50 =ll and >80 µM, respectively in a standard TRAP assay).

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Section: (B) a G-quartet (Left) And A Schematic Drawing Of An Intramentioning

confidence: 99%

Ascididemin and meridine stabilise G-quadruplexes and inhibit telomerase in vitro

Guittat

Cian

Rosu

et al. 2005

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…The non-folded, single-stranded form of the primer is required for optimal telomerase activity and qua-druplex formation has been shown to directly inhibit telomerase elongation in vitro [20]. A growing number of small molecules have been discovered to inhibit telomerase activ ity by inducing and/or stabilizing G-quartet structure [45,46], including l0H-indolo [3,2-b] quinoline derivatives [47]. Therefore, here, we performed a TRAP assay with increasing concentrations (ranging from 1 to 50 µM) of the compound.…”

Section: Telomerase Inhibitionmentioning

confidence: 99%

Interactions of cryptolepine and neocryptolepine with unusual DNA structures

et al. 2003

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1 These authors contributed equally to this work. AbstractCryptolepine, the main alkaloid present in the roots of Cryptolepis sanguinolenta, presents a large spectrum of biological properties. It has been reported to behave like a DNA intercalator with a preference for GC-rich sequences. In this study, dialysis competition assay and mass spectrometry experiments were used to determine the affinity of cryptolepine and neocryptolepine for DNA structures among duplexes, triplexes, quadruplexes and single strands. Our data confirm that cryptolepine and neocryptolepine prefer GC over AT-rich duplex sequences, but also recognize triplex and quadruplex structures. These compounds are weak telomerase inhibitors and exhibit a significant preference for triplexes over quadruplexes or duplexes.

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“…The best ligand 9 gave a ⌬T m of ϩ19.7°C, followed by 5, which gave a ⌬T m of ϩ12.5°C, whereas compound 7 gave a ⌬T m of only ϩ2.5°C. A number of small molecules have been discovered to inhibit the function of telomerase by stabilizing quadruplex DNA (G4-DNA) (29,30). The ⌬T m effect therefore was compared with telomerase inhibition efficiency.…”

Section: Identification Of G4-specific Ligandsmentioning

confidence: 99%

Telomerase inhibitors based on quadruplex ligands selected by a fluorescence assay

Mergny

Lacroix

Teulade‐Fichou

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

294

202

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The reactivation of telomerase activity in most cancer cells supports the concept that telomerase is a relevant target in oncology, and telomerase inhibitors have been proposed as new potential anticancer agents. The telomeric G-rich single-stranded DNA can adopt in vitro an intramolecular quadruplex structure, which has been shown to inhibit telomerase activity. We used a fluorescence assay to identify molecules that stabilize G-quadruplexes. Intramolecular folding of an oligonucleotide with four repeats of the human telomeric sequence into a G-quadruplex structure led to fluorescence excitation energy transfer between a donor (fluorescein) and an acceptor (tetramethylrhodamine) covalently attached to the 5 and 3 ends of the oligonucleotide, respectively. The melting of the G-quadruplex was monitored in the presence of putative G-quadruplex-binding molecules by measuring the fluorescence emission of the donor. A series of compounds (pentacyclic crescent-shaped dibenzophenanthroline derivatives) was shown to increase the melting temperature of the G-quadruplex by 2-20°C at 1 M dye concentration. This increase in Tm value was well correlated with an increase in the efficiency of telomerase inhibition in vitro. The best telomerase inhibitor showed an IC 50 value of 28 nM in a standard telomerase repeat amplification protocol assay. Fluorescence energy transfer can thus be used to reveal the formation of four-stranded DNA structures, and its stabilization by quadruplex-binding agents, in an effort to discover new potent telomerase inhibitors.telomere ͉ DNA structure ͉ G-quartet T elomerase was first identified in ciliates (1). This enzyme is an essential factor in immortalization and tumorigenesis (2-4). Furthermore, telomerase is active in most human tumor cells and inactive in most somatic cells and is therefore an attractive target for the design of anticancer agents. Most human telomeric DNA is double-stranded and contains (TTAGGG͞CCCTAA) n repeats except for the extreme terminal part where the 3Ј region of the G-rich strand is singlestranded (5). For human cells, these 3Ј overhangs are surprisingly long (averaging 130-210 bases in length), exist during most of the cell cycle, and are present on all chromosomal ends. The G-rich single-stranded DNA can adopt an unusual four-stranded DNA structure involving G-quartets (6-8) (see Fig. 1) or it might fold back and displace one strand of a telomeric duplex to form a so-called T-loop (9). Optimal telomerase activity requires the nonfolded single-stranded form of the primer and G-quartet formation has been shown to directly inhibit telomerase elongation in vitro (10). Therefore, a drug that stabilizes quadruplexes could interfere with telomerase and telomere replication (11-13).The peculiar geometry of the quadruplex structure should allow its specific recognition by small synthetic ligands, and previous experiments have shown that this assumption is correct (14). Many of the G4 ligands were shown to have antitelomerase activity in vitro, with IC 50 in the low micromo...

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G-Quadruplex DNA as a Target for Drug Design

Cited by 226 publications

References 181 publications

Ascididemin and meridine stabilise G-quadruplexes and inhibit telomerase in vitro

Ascididemin and meridine stabilise G-quadruplexes and inhibit telomerase in vitro

Interactions of cryptolepine and neocryptolepine with unusual DNA structures

Telomerase inhibitors based on quadruplex ligands selected by a fluorescence assay

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