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PubMedDate not supplied

PNA-DNA chimeras forming quadruplex structures.

1H-NMR, CD, and UV spectroscopy have been used to investigate the structure of PNA/DNA chimeras forming quadruplex structures. In particular, we synthesized 5'TGGG3'-t (1) and 5'TGG3'-gt (2), where lower and upper case letters indicate PNA and DNA residues, respectively. CD spectrum and all NMR data of (1) are typical of quadruplexes involving four parallel strands. UV melting profile of (1) indicates that its thermal stability is quite similar to that observed for the reference structure [d(TGGGT)]4. 1H-NMR spectrum for 5'TGG3'-gt (2) shows that this oligonucleotide is not able to fold into a single, well-defined species.

Base Sequence↗
PubMed2005

Unusual monomolecular DNA quadruplex structures using bunch-oligonucleotides.

The chemical synthesis of several G-rich bunch-oligonucleotides and the structural characterization of the corresponding monomolecular G-quadruplexes (I-IV) have been reported. The synthetic method allow the achievement of monomolecular DNA quadruplex structures having unusual and predeterminable oligodeoxyribonucleotide (ODN) strand orientation.

DNA↗
PubMed2005

Relative stability of quadruplexes containing different number of G-tetrads.

The aim of this work is to compare the physicochemical properties of three oligonucleotidic sequences, d(TGGGT), d(TGGGGT) and d(TGGGGGT), which assemble to form quadruplex structures with the same molecularity, but containing three, four, and five G-quartets, respectively. The addition of one or two G-tetrads greatly increases both the enthalpy and Tm values of the quadruplex dissociation.

Biophysical Phenomena↗
PubMed2003

Inhibition of human immunodeficiency virus 1 replication in vitro by a self-stabilized oligonucleotide with 2'-O-methyl-guanosine-uridine quadruplex motifs.

OBJECTIVES: Given that the guanosine-quadruplex may have a role in blocking the interaction between gp120 and CD4, we describe here the design of a highly nuclease-resistant dimeric hairpin guanosine-quadruplex, [Gm3Um4Gm3-s], containing the 2'-O-methyl groups on the nucleoside and sulphur groups on the internucleotidic bonds, and its anti-HIV-1 activity in cultured cells. METHODS: The unmodified and modified oligonucleotides were chemically synthesized. The anti-HIV activities of test compounds on HIV-1 infection were determined by protection against HIV-1-induced cytopathic effects. The mechanism of action of the oligonucleotides was determined by virus binding and detection [anti-CD4 monoclonal antibody (MAb) and anti-V3 MAb] assays. RESULTS: Gm3Um4Gm3-s was highly nuclease resistant, had significantly higher anti-HIV-1 activity than dG3T4G3-s, dG10-s and Gm10-s, and blocked the interaction between gp120 and CD4. CONCLUSION: The anti-HIV-1 activity of this oligonucleotide was increased when the phosphodiester and 2'-hydroxyl groups on the oligonucleotide backbones were replaced with a phosphorothioate and 2'-O-methyl backbone; thus Gm3Um4Gm3-s may inhibit HIV-1 infection, at least in part, by blocking the interaction between gp120 and CD4.

Anti-HIV Agents↗
PubMed2003

Platinum cross-linking of adenines and guanines on the quadruplex structures of the AG3(T2AG3)3 and (T2AG3)4 human telomere sequences in Na+ and K+ solutions.

The quadruplex structures of the human telomere sequences AG3(T2AG3)3 I and (T2AG3)4 II were investigated in the presence of Na+ and K+ ions, through the cross-linking of adenines and guanines by the cis- and trans-[Pt(NH3)2(H2O)2](NO3)2 complexes 1 and 2. The bases involved in chelation of the cis- and trans-Pt(NH3)2 moieties were identified by chemical and 3'-exonuclease digestions of the products isolated after denaturing gel electrophoresis. These are the four adenines of each sequence and four out of the 12 guanines. Two largely different structures have been reported for I: A from NMR data in Na+ solution and B from X-ray data of a K+-containing crystal. Structure A alone agrees with our conclusions about the formation of the A1-G10, A13-G22, A1-A13 platinum chelates at the top of the quadruplex and A7-A19, G4-A19 and A7-G20 at the bottom, whether the Na+ or K+ ion is present. At variance with a recent proposal that structures A and B could be the major species in Na+ and K+ solutions, respectively, our results suggest that structure A exists predominantly in the presence of both ions. They also suggest that covalent platinum cross-linking of a human telomere sequence could be used to inhibit telomerase.

Adenine↗
PubMed2003

DNA nanomotor using duplex-quadruplex conformational transition.

For DNA nanomotor, we synthesized 8-Py-dG and incorporated it into d(T3G2)4 which can form quadruplex. We measured CD spectra for this ODN. The result suggested that this ODN was changed from quadruplex to duplex by the hybridization with the complementary strand. Further, this ODN had a very interesting property of fluorescence. The fluorescent intensity could be controlled whether the complementary strand was existed, or not.

Base Sequence↗
PubMed2000

Properties of quadruplex oligonucleotides with anti-HIV-1 activity.

A phosphorothioate oligonucleotide composed of deoxyguanosine and thymidine was identified as an inhibitor of HIV-1 infection at an early stage of the HIV-1 replication cycle in vitro. The phosphodiester and phosphorothioate chimeric oligonucleotides were found to be potent inhibitors of several steps of HIV-1 infection: the interaction with CD4 and the chemokine receptor, the reverse transcriptase activity, and the integrase activity. To elucidate the mechanism of the anti-HIV-1 function of these oligonucleotides in terms of their structure, we focussed on their G-serial sequences and investigated the characteristics of their solution structures. These oligonucleotides were proved to be able to adopt G-quadruplex structures by UV and CD measurements. We presume that the anti-HIV-1 activities of these oligonucleotides are consequently attributable to G-quadruplex formation.

Anti-HIV Agents↗
PubMed2004

Biological activity of the G-quadruplex ligand RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate) is associated with telomere capping alteration.

This study had two goals: 1) to evaluate the biological effect of the novel pentacyclic acridine 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4) on human melanoma lines possessing long telomeres, and 2) to elucidate the relationship between G-quadruplex-based telomerase inhibitor-induced cellular effects and telomere length/dysfunction. The cellular pharmacological effects of RHPS4 have been evaluated by treating melanoma lines with increasing concentrations of RHPS4. A dose-dependent inhibition of cell proliferation was observed in all the lines during short-term treatment. Flow cytometric analysis demonstrated that RHPS4 induced a dose-dependent accumulation of cells in the S-G(2)/M phase of cell cycle. The RHPS4-induced cell cycle alteration was irreversible even at low doses, and the cells died from apoptosis. At high RHPS4 concentration, apoptosis was accompanied by the induction of a senescence phenotype: large cell size, vacuolated cytoplasm, and beta-galactosidase activity. The short-term biological activity of RHPS4 was not caused by telomere shortening, but it was associated with telomere dysfunction, in terms of presence of telomeric fusions, polynucleated cells, and typical images of telophase bridge. In conclusion, our results demonstrate that the G-quadruplex ligand RHPS4 can function in a telomere length-independent manner through its ability to cause telomere-capping alteration.

Acridines↗
PubMed2004

G-quadruplex interacting agents targeting the telomeric G-overhang are more than simple telomerase inhibitors.

The extremities of chromosomes end at telomeres in a G-rich single stranded overhang that may adopt peculiar structures such as T-loop and G-quadruplex. G-quadruplex is a poor substrate for telomerase activity and different classes of small molecule ligands that selectively stabilize this structure and inhibit telomerase activity have been selected by screening or synthesized by oriented chemistry. These ligands differ from catalytic inhibitors of telomerase by several points that were discussed in the present review, with a special emphasis on their biological activity as potential antitumor agents.

Antineoplastic Agents↗
PubMed2003

Detection and typing of HSV-1, HSV-2, CMV and EBV by quadruplex PCR.

The development of a multiplex polymerase chain reaction (PCR) method for rapid and accurate detection and typing of herpes simplex virus type 1 (HSV-1), and type-2 (HSV-2), cytomegalovirus (CMV) and Epstein-Barr virus (EBV) is very important for clinical diagnosis to allow the deliver of therapy as early as possible. Large scale amplifications by multiplex PCR of viral DNA can lower the cost and time for viral diagnosis. In this study, therefore sensitive quadruplex PCR was achieved by optimizing parameters such as primers, and 1.5 mM magnesium and 200 uM dNTPs concentrations. The concentrations of HSV-1, HSV-2, CMV and EBV primers were 0.5, 0.3, 0.25 and 0.25 pmoles, respectively. Optimal annealing temperature was 54 degrees C. Employing these conditions, we could detect 10 copies of reconstructed template plasmid DNA, which were cloned to vectors containing target sequences of viral DNA. PCR products of 271 bp for HSV-1, 231 bp for HSV-2, 368 bp for CMV, and 326 bp for EBV were separated on 5.0% polyacrylamide gel electrophoresis and confirmed by direct sequencing. The present study showed that the quadruplex PCR assay described herein has potential application in clinical diagnosis, when rapid, accurate detection and typing of viruses HSV-1, HSV-2, CMV or EBV are necessary.

Cytomegalovirus↗
PubMed2004

A G-quadruplex-interactive agent, telomestatin (SOT-095), induces telomere shortening with apoptosis and enhances chemosensitivity in acute myeloid leukemia.

Telomerase, the ribonucleoprotein enzyme maintaining the telomeres of eukaryotic chromosomes, is up-regulated in the vast majority of human neoplasias but not in normal somatic tissues. Therefore, the telomerase complex represents a promising universal therapeutic target in cancer. Telomeric G-rich single-stranded DNA can adopt in vitro an intramolecular quadruplex structure, which has been shown to inhibit telomerase activity. We examined G-quadruplex interactive agent, telomestatin (SOT-095), for its ability to inhibit the proliferation of human leukemia cells, including freshly obtained leukemia cells. Telomere length was determined by either the terminal restriction fragment method or flow-FISH, and apoptosis was assessed by flow cytometry. Moreover, chemosensitivity was examined in telomestatin-treated U937 cells before ultimate telomere shortening. Treatment with telomestatin reproducibly inhibited telomerase activity in U937 and NB4 cells followed by telomere shortening. Enhanced chemosensitivity toward daunorubicin and cytosine-arabinoside was observed in telomestatin-treated U937 cells, before ultimate telomere shortening. Telomere shortening associated with apoptosis by telomestatin was evident in some freshly obtained leukemia cells from acute myeloid leukemia patients, regardless of sub-types of AML and post-myelodysplasia AML. These results suggest that disruption of telomere maintenance by telomestatin limits the cellular lifespan of AML cells, as well. However, in a minority of AML patients apoptosis was not evident, thus indicating that resistant mechanism might exist in some freshly obtained AML cells. Therefore, further investigation of telomestatin as a therapeutic agent is warranted.

Acute Disease↗
PubMed2026

Oxidative Damage Fine-Tunes G-Quadruplex Structures in Human Gene Promoters.

Oxidative damage can convert guanine (G) into 8-oxoguanine (O8G), resulting in altered gene expression and genome instability. However, the underlying molecular mechanisms remain poorly understood. Herein, we show that the NEIL3 gene proximal promoter sequence forms a mixture of parallel and hybrid G-quadruplex structures (NEIL3-G4s), exhibiting intrinsic structural polymorphism. Strikingly, site-specific O8G modifications significantly reduce this polymorphism, promoting the stabilization of either the parallel or the (3+1) hybrid-1 G4 topology. A single G-to-O8G substitution is sufficient to trigger a clear structural transition from the parallel to the (3+1) hybrid-1 G4, highlighting the profound impact of O8G on G4-mediated epigenetic regulation. We have determined the NMR solution structures of both native and O8G-modified NEIL3-G4s, providing mechanistic insights into how O8G induces specific G4 structural rearrangements. Functional analysis demonstrates that both forms of NEIL3-G4s can form in extended DNA contexts and inhibit DNA polymerase activity. Under oxidative stress, the formation of NEIL3-G4s correlates with elevated NEIL3 gene expression, suggesting that they play a role as sensors of oxidative damage and function as molecular switches for gene upregulation. Collectively, these findings underscore the crucial role of O8G-induced G4 structural plasticity in the cellular response to oxidative stress and in regulating gene expression.

G-Quadruplexes↗
PubMed2026

Unraveling G-Quadruplex and i-Motif Coexistence Within a Double-Stranded DNA.

DNA can transiently fold into variable arrangements, which are expected to exploit regulatory functions. Guanine-rich sequences can fold into G-quadruplexes (G4s), while the complementary strand adopts potentially i-Motif (iM) arrangements. Their concomitant formation at the same genomic site is still under debate. However, recently, single-molecule analyses have shown the simultaneous G4 and iM presence within a double-stranded (ds) DNA context, addressing them as synergic blockers of replication fork progression. While these findings point to a functional interplay between G4 and iM, a deeper understanding of the factors enabling their coexistence remains unclear. In this work, we unravel the equilibria governing G4- and iM-folding within dsDNA, adopting an extensive biophysical approach allowing analysis of an optimized modular system, scalable across constructs of increasing molecular complexity. Our findings corroborate the simultaneous formation model and further clarify the thermodynamic determinants driving duplex denaturation and the favorable folding of stable G4 and iM structures.

G-Quadruplexes↗
PubMed2026

A G-Quadruplex-Activated Near-Infrared Chemiluminescent Probe for In Situ Hepatic Imaging of the Hepatitis C Virus Genome.

Real-time monitoring of viral replication is essential for infectious disease diagnosis and antiviral drug development. The G-quadruplex (G4), a conserved regulatory element within viral genomes, represents a significant endogenous biomarker for tracking viral activity. However, imaging viral G4s in deep tissues remains a challenge for current optical technologies due to severe photon attenuation and autofluorescence. Herein, we report Lumin680, the first near-infrared (NIR) chemiluminescent probe directly activated by conserved viral G4 conformations. Its chemiluminescence was triggered by parallel G4, emitting in the NIR optical window (680 nm) with a 104.6-fold signal enhancement. Notably, the luminescence of Lumin680 could penetrate up to 1.2 cm of biological tissue, outperforming traditional G4 fluorescent probe. In vivo, Lumin680 enabled the rapid visualization of orthotopic hepatitis C virus (HCV) genome RNA-presenting mini-organ within 5 min post-intravenous administration. Furthermore, the chemiluminescent intensity of Lumin680 quantitatively mapped the therapeutic efficacy of clinical direct-acting antivirals (DAAs) at both the cellular and whole-animal levels, exhibiting high concordance with the gold-standard quantitative RT-PCR (qPCR). This study not only provides a powerful G4 specific chemiluminescent tool but also establishes a novel paradigm for the non-invasive, in situ diagnosis and precise therapeutic monitoring of viral infections.

G-Quadruplexes↗
PubMed2026

Structure-based drug design of small-molecule c-Myc G-quadruplex binders.

The c-Myc oncogene is crucial in tumorigenesis. Although it is a promising therapeutic target, its protein lacks a conventional drug-binding pocket, making it traditionally "undruggable". Recent studies show that the c-Myc promoter can form a G-quadruplex (G4) structure, which suppresses transcription and offers a new strategy for indirect inhibition. In this study, structure-based virtual screening was performed using the c-Myc G4 crystal structure to screen the ChemDiv compound library, aiming to identify small molecules that bind to the G4 structure. Candidate compounds were evaluated in preliminary in vitro assays for biological activity. The results showed that Y502-3888 binds to the c-Myc G4 and downregulates c-Myc expression at both mRNA and protein levels. Collectively, these findings support the potential of Y502-3888 as a c-Myc G4 binder for the treatment of multiple myeloma (MM), providing a foundation for future development of anticancer agents targeting the c-Myc G4.

G-Quadruplexes↗
PubMed2024

Viral hijacking of hnRNPH1 unveils a G-quadruplex-driven mechanism of stress control.

Viral genomes are enriched with G-quadruplexes (G4s), non-canonical structures formed in DNA or RNA upon assembly of four guanine stretches into stacked quartets. Because of their critical roles, G4s are potential antiviral targets, yet their function remains largely unknown. Here, we characterize the formation and functions of a conserved G4 within the polymerase coding region of orthoflaviviruses of the Flaviviridae family. Using yellow fever virus, we determine that this G4 promotes viral replication and suppresses host stress responses via interactions with hnRNPH1, a host nuclear protein involved in RNA processing. G4 binding to hnRNPH1 causes its cytoplasmic retention with subsequent impacts on G4-containing tRNA fragments (tiRNAs) involved in stress-mediated reductions in translation. As a result, these host stress responses and associated antiviral effects are impaired. These data reveal that the interplay between hnRNPH1 and both host and viral G4 targets controls the integrated stress response and viral replication.

Animals↗
PubMed2026

G-quadruplex upstream of PAX9 TSS acts as a 3D-genome scaffold to remotely silence X-linked genes and modulate cell-cycle progression.

G-quadruplexes (G4s) are non-canonical DNA secondary structures that act as local replication barriers and transcriptional regulators. Whether G4 can simultaneously influence splicing, DNA replication, and long-range, trans-chromosomal gene regulation remains untested. Here we combined in vitro biophysics, CRISPR mutagenesis and multi-omics to dissect a conserved G4 motif (QS1) located ~173 bp upstream of the PAX9 transcription start site. CD spectroscopy confirmed that the wild-type, but not the G-to-T mutant sequence, folds into a stable parallel G4 under physiological K+. In human cells, disruption of the QS1 G4 changed chromatin accessibility, remotely down-regulated a cohort of X-linked genes, accelerated migration and delayed G1/S progression. Integrative analysis of ATAC-seq, RNA-seq profiling reveals that the QS1 G4 acts as a three-dimensional genome scaffold linking PAX9 to cell-cycle and metabolic networks. Our findings establish a pleiotropic role for a single promoter G4 in coordinating DNA replication stress, chromatin architecture and trans-chromosomal transcriptional control.

G-Quadruplexes↗