A Phenotypic Approach to the Discovery of Potent G-Quadruplex Targeted Drugs

Molecules, Год журнала: 2024, Номер 29(15), С. 3653 - 3653

Опубликована: Авг. 1, 2024

G-quadruplex (G4) sequences, which can fold into higher-order G4 structures, are abundant in the human genome and over-represented promoter regions of many genes involved cancer initiation, progression, metastasis. They plausible targets for G4-binding small molecules, would, case G4s, result transcriptional downregulation these genes. However, structural information is currently available on only a very number G4s their ligand complexes. This limitation, coupled with restricted G4-containing most complex cancers, has led to development phenotypic-led approach drug discovery. was illustrated by discovery several generations tri- tetra-substituted naphthalene diimide (ND) ligands that were found show potent growth inhibition pancreatic cell lines active vivo models this hard-to-treat disease. The cycles have culminated highly ND derivative, QN-302, being evaluated Phase 1 clinical trial. major whose expression been down-regulated QN-302 presented here: all contain propensity be up-regulated cancer. Some also upregulated other supporting hypothesis pan-G4 potential utility beyond

Язык: Английский

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Structural Unfolding of G-Quadruplexes: From Small Molecules to Antisense Strategies

Molecules, Год журнала: 2024, Номер 29(15), С. 3488 - 3488

Опубликована: Июль 25, 2024

G-quadruplexes (G4s) are non-canonical nucleic acid secondary structures that have gathered significant interest in medicinal chemistry over the past two decades due to their unique structural features and potential roles a variety of biological processes disorders. Traditionally, research efforts focused on stabilizing G4s, while recent years, attention has progressively shifted G4 destabilization, unveiling new therapeutic perspectives. This review provides an in-depth overview advances development small molecules, starting with controversial role TMPyP4. Moreover, we described effective metal complexes addition G4-disrupting molecules as well good ligands can destabilize G4s response external stimuli. Finally, presented antisense strategies promising approach for destabilizing particular focus 2'-OMe oligonucleotide, peptide acid, locked acid. Overall, this emphasizes importance understanding dynamics ongoing develop selective G4-unfolding modulate function potential.

Язык: Английский

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Unveiling a Novel RNA G-Triplex Structure: Its Function and Potential in CRISPR-based Diagnostics

Chemical Communications, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

The truncated TERRA sequence [UUAGGG] 3 forms a stable parallel RNA G-triplex structure and can be used as novel biosensing element.

Язык: Английский

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Self-contained G-quadruplex/hemin DNAzyme: a superior ready-made catalyst for in situ imaging analysis

Nucleic Acids Research, Год журнала: 2025, Номер 53(6)

Опубликована: Март 20, 2025

Abstract The G4 DNAzyme holds significant potential for applications in bioanalysis and determination owing to its peroxidase mimetic activity DNA programmability. However, clinical practicability is constrained by limited catalytic supplementary assembly requirements, attributed weak π–π stacking, deficient active-site components, ion-dependent mechanisms. Thus, we constructed a highly active self-contained intramolecular G4/hemin through the direct covalent cross-linking of core components involving hemin prosthetic group, pocket, distal ligand-like assistant nucleotide (adenine or cytosine). Detailed investigations efficiency mechanism confirmed formation compact center bonding, which enhanced catalysis stage comparable that horseradish localized surroundings. superior ready-made modularity with programmability enabled sensitive situ imaging analysis HER2 protein breast cancer specimens. This study provides powerful tool disease marker detection high sensitivity immediate availability.

Язык: Английский

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The entangled world of DNA quadruplex folds

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 22, 2024

Abstract DNA quadruplexes take part in many biological functions. It takes up a variety of folds based on the sequence and environment. Here, meticulous analysis experimentally determined 392 quadruplex structures (388 PDB IDs) deposited is carried out. The reveals modular representation folds. 48 unique motifs (whose diversity arises out propeller, bulge, diagonal, lateral loops that connect quartets) are identified, leading to simple complex inter-/intra-molecular These structural two-layered further classified into 33 continuous 15 discontinuous motifs. cannot be parallel, antiparallel, or hybrid as one more guanines adjacent quartets not connected. While can extended fold, motif requires additional loop(s) complete illustrated here with examples. Similarly, higher-order also represented by their combinations. Such may assist custom engineering quadruplexes, designing motif-based drugs, prediction structure. Further, it could facilitate understanding role functions diseases.

Язык: Английский

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Quinoline based viologen as a multifunctional organic material – From crystal structures to photophysical and electrochemical properties, and application in DNA sensing and bioimaging

Journal of Photochemistry and Photobiology A Chemistry, Год журнала: 2024, Номер 454, С. 115735 - 115735

Опубликована: Май 3, 2024

Язык: Английский

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The Characterization of G-Quadruplexes in Tobacco Genome and Their Function under Abiotic Stress

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(8), С. 4331 - 4331

Опубликована: Апрель 14, 2024

Tobacco is an ideal model plant in scientific research. G-quadruplex a guanine-rich DNA structure, which regulates transcription and translation. In this study, the prevalence potential function of G-quadruplexes tobacco were systematically analyzed. genomes, there 2,924,271,002 nuclear genome, 430,597 mitochondrial 155,943 chloroplast genome. The density organelle genome was higher than that abundant regulatory region difference two strands also observed. promoter 60.4% genes contained at least one G-quadruplex. Compared with up-regulated differentially expressed (DEGs), down-regulated DEGs generally under drought stress salt stress. formed by simple sequence repeat (SSR) its flanking NtBBX (Nitab4.5_0002943g0010) gene might enhance tolerance tobacco. This study lays solid foundation for further research on other plants.

Язык: Английский

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Novel Therapeutic Horizons: SNCA Targeting in Parkinson’s Disease

Biomolecules, Год журнала: 2024, Номер 14(8), С. 949 - 949

Опубликована: Авг. 6, 2024

Alpha-synuclein (αSyn) aggregates are the primary component of Lewy bodies, which pathological hallmarks Parkinson’s disease (PD). The toxicity αSyn seems to increase with its elevated expression during injury, suggesting that therapeutic approaches focused on reducing burden in neurons could be beneficial. Additionally, studies have shown higher levels SNCA mRNA midbrain tissues and substantia nigra dopaminergic sporadic PD post-mortem brains compared controls. Therefore, regulation inhibition synthesis play an important role pathogenesis resulting effective treatment approach for PD. In this context, we summarized most recent innovative strategies proposed exploit targeting regulate translation efficiently knock down cytoplasmatic αSyn. Significant progress has been made developing antisense technologies treating years, a focus oligonucleotides short-interfering RNAs, achieve high specificity towards desired target. To provide more exhaustive picture research field, also reported less common but highly strategies, including small molecules, designed specifically bind 5′-untranslated regions and, secondary nucleic acid structures present gene, whose formation can modulated, acting as transcription control. fully describe efficiency effect reduction cellular viability dopamine homeostasis was considered.

Язык: Английский

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Entangled World of DNA Quadruplex Folds

ACS Omega, Год журнала: 2024, Номер 9(37), С. 38696 - 38709

Опубликована: Сен. 5, 2024

DNA quadruplexes participate in many biological functions. It takes up a variety of folds based on the sequence and environment. Here, meticulous analysis experimentally determined 437 quadruplex structures (433 PDBs) deposited PDB is carried out. The reveals modular representation folds. Forty-eight unique motifs (whose diversity arises out propeller, bulge, diagonal, lateral loops that connect quartets) are identified, leading to simple complex inter/intramolecular two-layered structural further classified into 33 continuous 15 discontinuous motifs. While can directly be extended fold, motif requires an additional loop(s) complete as illustrated here with examples. Similarly, higher-order also represented by or their combinations. Such may assist custom engineering quadruplexes, designing motif-based drugs, prediction structure. Furthermore, it could facilitate understanding role functions diseases.

Язык: Английский

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Selective recognition of RNA G-quadruplex in vitro and in cells by L-aptamer–D-oligonucleotide conjugate

Nucleic Acids Research, Год журнала: 2024, Номер 52(22), С. 13544 - 13560

Опубликована: Ноя. 18, 2024

Abstract RNA Guanine-quadruplexes (rG4s) are important nucleic acid structures that govern vital biological processes. Although numerous tools have been developed to target rG4s, few specific capable of discerning individual rG4 interest. Herein, we design and synthesize the first L-aptamer–antisense oligonucleotide (ASO) conjugate, L-Apt.4–1c-ASO15nt(APP), with a focus on recognizing amyloid precursor protein (APP) region as an example. The L-aptamer module binds structure, whereas ASO hybridizes flanking sequences. Together, these two modules enhance precise recognition APP rG4. We demonstrate L-Apt.4–1c-ASO15nt(APP) conjugate can interact sub-nanomolar binding affinity, distinguish from other G4s non-G4s in vitro cells. also show inhibit expression. Notably, investigate inhibitory mechanism this newly tool, reveal it controls gene expression by hindering DHX36 unraveling rG4, well promoting translational inhibition RNase H-mediated mRNA knockdown activity. Our novel L-aptamer–ASO tool not only enables interest, but allows efficient control via targeting rG4-containing transcripts

Язык: Английский

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