共查询到20条相似文献,搜索用时 31 毫秒
1.
Looking for Efficient G‐Quadruplex Ligands: Evidence for Selective Stabilizing Properties and Telomere Damage by Drug‐Like Molecules
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Dr. Bruno Pagano Dr. Jussara Amato Nunzia Iaccarino Dr. Chiara Cingolani Dr. Pasquale Zizza Dr. Annamaria Biroccio Prof. Ettore Novellino Prof. Antonio Randazzo 《ChemMedChem》2015,10(4):640-649
There is currently significant interest in the development of G‐quadruplex‐interactive compounds, given the relationship between the ability to stabilize these non‐canonical DNA structures and anticancer activity. In this study, a set of biophysical assays was applied to evaluate the binding of six drug‐like ligands to DNA G‐quadruplexes with different folding topologies. Interestingly, two of the investigated ligands showed selective G‐quadruplex‐stabilizing properties and biological activity. These compounds may represent useful leads for the development of more potent and selective ligands. 相似文献
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Balayeshwanth R. Vummidi Dr. Jawad Alzeer Prof. Dr. Nathan W. Luedtke 《Chembiochem : a European journal of chemical biology》2013,14(5):540-558
Mounting evidence supports the presence of biologically relevant G‐quadruplexes in single‐cell organisms, but the existence of endogenous G‐quadruplex structures in mammalian cells remains highly controversial. This is due, in part, to the common misconception that DNA and RNA molecules are passive information carriers with relatively little structural or functional complexity. For those working in the field, however, the lack of available tools for characterizing DNA structures in vivo remains a major limitation to addressing fundamental questions about structure–function relationships of nucleic acids. In this review, we present progress towards the direct detection of G‐quadruplex structures by using small molecules and modified oligonucleotides as fluorescent probes. While most development has focused on cell‐permeable probes that selectively bind to G‐quadruplex structures with high affinity, these same probes can induce G‐quadruplex folding, thereby making the native conformation of the DNA or RNA molecule (i.e., in the absence of probe) uncertain. For this reason, modified oligonucleotides and fluorescent base analogues that serve as “internal” fluorescent probes are presented as an orthogonal means for detecting conformational changes, without necessarily perturbing the equilibria between G‐quadruplex, single‐stranded, and duplex DNA. The major challenges and motivation for the development of fluorescent probes for G‐quadruplex structures are presented, along with a summary of the key photophysical, biophysical, and biological properties of reported examples. 相似文献
4.
Development of Fluorescent Protein Probes Specific for Parallel DNA and RNA G‐Quadruplexes
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Dr. Dung Thanh Dang Prof. Dr. Anh Tuân Phan 《Chembiochem : a European journal of chemical biology》2016,17(1):42-45
We have developed fluorescent protein probes specific for parallel G‐quadruplexes by attaching cyan fluorescent protein to the G‐quadruplex‐binding motif of the RNA helicase RHAU. Fluorescent probes containing RHAU peptide fragments of different lengths were constructed, and their binding to G‐quadruplexes was characterized. The selective recognition and discrimination of G‐quadruplex topologies by the fluorescent protein probes was easily detected by the naked eye or by conventional gel imaging. 相似文献
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Multivalent Interactions between an Aromatic Helical Foldamer and a DNA G‐Quadruplex in the Solid State
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Dr. Pradeep K. Mandal Dr. Benoît Baptiste Dr. Béatrice Langlois d'Estaintot Dr. Brice Kauffmann Dr. Ivan Huc 《Chembiochem : a European journal of chemical biology》2016,17(20):1911-1914
Quinoline‐based oligoamide foldamers have been identified as a potent class of ligands for G‐quadruplex DNA. Their helical structure is thought to target G‐quadruplex loops or grooves and not G‐tetrads. We report a co‐crystal structure of the antiparallel hairpin dimeric DNA G‐quadruplex (G4T4G4)2 with tetramer 1 —a helically folded oligo‐quinolinecarboxamide bearing cationic side chains—that is consistent with this hypothesis. Multivalent foldamer–DNA interactions that modify the packing of (G4T4G4)2 in the solid state are observed. 相似文献
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Fluorescent Dansyl‐Guanosine Conjugates that Bind c‐MYC Promoter G‐Quadruplex and Downregulate c‐MYC Expression
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Y. Pavan Kumar Puja Saha Dhurjhoti Saha Irene Bessi Prof. Dr. Harald Schwalbe Dr. Shantanu Chowdhury Prof. Dr. Jyotirmayee Dash 《Chembiochem : a European journal of chemical biology》2016,17(5):388-393
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Andrea Funke Beatrice Karg Dr. Jonathan Dickerhoff Dr. Darko Balke Prof. Dr. Sabine Müller Prof. Dr. Klaus Weisz 《Chembiochem : a European journal of chemical biology》2018,19(5):505-512
Binding of an indoloquinoline derivative with an aminoalkyl side chain to a truncated sequence from the MYC promoter region was studied through isothermal titration calorimetry (ITC). The targeted MYC3 sequence lacks 3′‐flanking nucleotides and forms a monomeric parallel quadruplex (G4) with a blunt‐ended 3′‐outer tetrad under the solution conditions employed. Analysis of ITC isotherms reveals multiple binding equilibria with the initial formation of a 1:2 ligand/quadruplex complex. Evaluation of electrophoretic mobilities as well as NMR spectral data confirm ligand‐induced dimerization of MYC3 quadruplexes with the ligand sandwiched between the two 3′‐outer tetrads. Additional ligand molecules in excess bind to the 5′‐outer tetrads of the sandwich complex. Such a ligand‐promoted G4 dimerization may be exploited for the controlled assembly or disassembly of G4 aggregates to expand on present quadruplex‐based technologies. 相似文献
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Osman Doluca Prof. Dr. Alexandre S. Boutorine Dr. Vyacheslav V. Filichev 《Chembiochem : a European journal of chemical biology》2011,12(15):2365-2374
The majority of studies on DNA triple helices have been focused on pH‐sensitive parallel triplexes with Hoogsteen CT‐containing third strands that require protonation of cytosines. Reverse Hoogsteen GT/GA‐containing antiparallel triplex‐forming oligonucleotides (TFOs) do not require an acidic pH but their applicability in triplex technology is limited because of their tendency to form undesired highly stable aggregates such as G‐quadruplexes. In this study, G‐rich oligonucleotides containing 2–4 insertions of twisted intercalating nucleic acid (TINA) monomers are demonstrated to disrupt the formation of G‐quadruplexes and form stable antiparallel triplexes with target DNA duplexes. The structure of TINA‐incorporated oligonucleotides was optimized, the rules of their design were established and the optimal triplex‐forming oligonucleotides were selected. These oligonucleotides show high affinity towards a 16 bp homopurine model sequence from the HIV‐1 genome; dissociation constants as low as 160 nM are observed whereas the unmodified TFO does not show any triplex formation and instead forms an intermolecular G‐quadruplex with Tm exceeding 90 °C in the presence of 50 mM NaCl. Here we present a set of rules that help to reach the full potential of TINA‐TFOs and demonstrate the effect of TINA on the formation and stability of triple helical DNA. 相似文献
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Prachi Agarwala Satyaprakash Pandey Dr. Souvik Maiti 《Chembiochem : a European journal of chemical biology》2013,14(16):2077-2081
With the potential to engineer biological systems, synthetic biology is an emerging field that combines various disciplines of sciences. It encompasses combinations of DNA, RNA and protein modules for constructing desired systems and the “rewiring” of existing signalling networks. Despite recent advances, this field still lags behind in the artificial reconstruction of cellular processes, and thus demands new modules and switches to create “genetic circuits”. The widely characterised noncanonical nucleic acid secondary structures, G‐quadruplexes are promising candidates to be used as biological modules in synthetic biology. Structural plasticity and functional versatility are significant G‐quadruplex traits for its integration into a biological system and for diverse applications in synthetic circuits. 相似文献
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De Cian A Grellier P Mouray E Depoix D Bertrand H Monchaud D Teulade-Fichou MP Mergny JL Alberti P 《Chembiochem : a European journal of chemical biology》2008,9(16):2730-2739
The increasing resistance of Plasmodium falciparum to the most commonly used antimalarial drugs makes it necessary to identify new therapeutic targets. The telomeres of the parasite could constitute an attractive target. They are composed of repetitions of a degenerate motif ((5')GGGTTYA(3'), where Y is T or C), different from the human one ((5')GGGTTA(3')). In this report we investigate the possibility of targeting Plasmodium telomeres with G-quadruplex ligands. Through solution hybridisation assays we provide evidence of the existence of a telomeric 3' G-overhang in P. falciparum genomic DNA. Through UV spectroscopy studies we demonstrate that stable G-quadruplex structures are formed at physiological temperature by sequences composed of the degenerate Plasmodium telomeric motif. Through a FRET melting assay we show stabilisation of Plasmodium telomeric G-quadruplexes by a variety of ligands. Many of the tested ligands display strong quadruplex versus duplex selectivity, but show little discrimination between human and Plasmodium telomeric quadruplexes. 相似文献
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G‐Quadruplexes with Tetra(ethylene glycol)‐Modified Deoxythymidines are Resistant to Nucleases and Inhibit HIV‐1 Reverse Transcriptase
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Dr. Hisae Tateishi‐Karimata Dr. Takahiro Muraoka Prof. Kazushi Kinbara Prof. Dr. Naoki Sugimoto 《Chembiochem : a European journal of chemical biology》2016,17(15):1399-1402
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Ana Rita Duarte Enrico Cadoni Dr. Ana S. Ressurreição Prof. Dr. Rui Moreira Prof. Dr. Alexandra Paulo 《ChemMedChem》2018,13(9):869-893
Guanine‐rich nucleic acid sequences able to form four‐stranded structures (G‐quadruplexes, G4) play key cellular regulatory roles and are considered as promising drug targets for anticancer therapy. On the basis of the organization of their structural elements, G4 ligands can be divided into three major families: one, fused heteroaromatic polycyclic systems; two, macrocycles; three, modular aromatic compounds. The design of modular G4 ligands emerged as the answer to achieve not only more drug‐like compounds but also more selective ligands by targeting the diversity of the G4 loops and grooves. The rationale behind the design of a very comprehensive set of ligands, with particular focus on the structural features required for binding to G4, is discussed and combined with the corresponding biochemical/biological data to highlight key structure–G4 interaction relationships. Analysis of the data suggests that the shape of the ligand is the major factor behind the G4 stabilizing effect of the ligands. The information here critically reviewed will certainly contribute to the development of new and better G4 ligands with application either as therapeutics or probes. 相似文献
14.
Expanding the Potential of G‐Quadruplex Structures: Formation of a Heterochiral TBA Analogue
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Dr. Antonella Virgilio Prof. Michela Varra Dr. Maria Scuotto Dr. Antonella Capuozzo Dr. Carlo Irace Prof. Luciano Mayol Dr. Veronica Esposito Prof. Aldo Galeone 《Chembiochem : a European journal of chemical biology》2014,15(5):652-655
In order to expand the potential applications of G‐quadruplex structures, we explored the ability of heterochiral oligodeoxynucleotides based on the thrombin‐binding aptamer (TBA) sequence to fold into similar complexes, with particular focus on their resistance in biological environments. A combination of CD and NMR techniques was used. Similarly to TBA, the ODN ggTTggtgtggTTgg (lower case letters indicate L residues) is able to fold into a chair‐like antiparallel G‐quadruplex structure, but has a slightly higher thermal stability. The discovery that heterochiral ODNs are able to form stable G‐quadruplex structures opens up new possibilities for their development in several fields, as aptamers, sensors and, as recently shown, as catalysts for enantioselective reactions. 相似文献
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Strand Invasion of DNA Quadruplexes by PNA: Comparison of Homologous and Complementary Hybridization
Dr. Anisha Gupta Ling‐Ling Lee Dr. Subhadeep Roy Farial A. Tanious Dr. W. David Wilson Dr. Danith H. Ly Dr. Bruce A. Armitage 《Chembiochem : a European journal of chemical biology》2013,14(12):1476-1484
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Dr. Xiu‐Ying Qin Dr. Ya‐Nan Liu Dr. Qian‐Qian Yu Dr. Li‐Cong Yang Ying Liu Dr. Yan‐Hui Zhou Prof. Dr. Jie Liu 《ChemMedChem》2014,9(8):1665-1671
A novel copper(II) complex with mixed ligands including β‐[(3‐formyl‐5‐methyl‐2‐hydroxy‐benzylidene)amino]propionic acid anion and 1,10′‐phenanthroline was synthesized, and its crystal structure was thoroughly characterized. It exerted excellent inducing apoptosis, anti‐angiogenesis and antiproliferative properties in vitro. The complex can bind human serum albumin (HSA) at physiological pH conditions. Remarkably, it can induce formation of the mixed parallel/antiparallel G‐quadruplex structures in the G‐rich sequence of the proximal vascular endothelial growth factor (VEGF) promoter, and stabilize these G‐quadruplex structures, which provide an opportunity for anti‐angiogenesis chemotherapeutics. Furthermore, the complex showed a strong uptake, and exhibited multiple anticancer functions by inhibiting the expression of p‐Akt and p‐Erk1/2 proteins and by upregulating the levels of reactive oxygen species (ROS). Because of the reported results, this new copper(II) complex qualifies itself as a potential anticancer drug candidate. 相似文献
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Dr. Jonathan Dickerhoff Prof. Dr. Klaus Weisz 《Chembiochem : a European journal of chemical biology》2018,19(9):927-930
A (3+1)‐hybrid‐type G‐quadruplex was substituted within its central tetrad by a single 2′‐fluoro‐modified guanosine. Driven by the anti‐favoring nucleoside analogue, a novel quadruplex fold with inversion of a single G‐tract and conversion of a propeller loop into a lateral loop emerges. In addition, scalar couplings across hydrogen bonds demonstrate the formation of intra‐ and inter‐residual F ??? H8?C8 pseudo‐hydrogen bonds within the modified quadruplexes. Alternative folding can be rationalized by the impact of fluorine on intermediate species on the basis of a kinetic partitioning mechanism. Apparently, chemical or other environmental perturbations are able to redirect folding of a quadruplex, possibly modulating its regulatory role in physiological processes. 相似文献
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L Stefan B Bertrand P Richard P Le Gendre F Denat M Picquet D Monchaud 《Chembiochem : a European journal of chemical biology》2012,13(13):1905-1912
The targeting of higher-order DNA structures has been thoroughly developed with G-quadruplex DNA but not with other structures like branched DNA (also known as DNA junctions). Because these alternative higher-order DNA architectures might be of high biological relevance, we implemented a high-throughput version of the FRET melting assay that enabled us to map the interactions of a candidate with four different DNA structures (duplex- and quadruplex DNA, three- and four-way junctions) in a rapid and reliable manner. We also introduce a novel index, the BONDS (branched and other noncanonical DNA selectivity) index, to conveniently quantify this differential affinity. 相似文献