RNA-Activatable Near-Infrared Photosensitizer for Cancer Therapy

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(36), С. 25270 - 25281

Опубликована: Авг. 31, 2024

Photodynamic therapy (PDT) has recently come to the forefront as an exceptionally powerful and promising method for treatment of cancer. Existing photosensitizers are predominantly engineered target diverse biomolecules, including proteins, DNA, lipids, carbohydrates, have proven greatly enhance efficacy or specificity PDT. However, it is noteworthy that there exists a conspicuous scarcity specifically designed RNAs. Recognizing crucial multifaceted roles played by RNAs in various cellular processes disease states, we ventured into development novel RNA-targeting photosensitizer, named Se-718, PDT-based cancer therapy. Se-718 been exhibit high molar absorption coefficient NIR region, which effective More importantly, demonstrated distinct capability, evidenced through rigorous testing both circular dichroism fluorescence experiments. Furthermore, shown display type I II photodynamic properties. This unique characteristic enables efficient killing cells under wide range oxygen conditions, normoxic (21% O2) hypoxic (2% O2). The IC50 can be low 100 nM, its light-to-dark toxicity ratio impressive 215 times higher, outperforming most currently available. Moreover, vivo studies conducted with tumor-bearing mice excellent antitumor effects safety profile Se-718. Considering outstanding PDT optimistic may provide innovative highly option therapeutics near future.

Язык: Английский

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G-quadruplexes promote the motility in MAZ phase-separated condensates to activate CCND1 expression and contribute to hepatocarcinogenesis

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Фев. 5, 2024

Abstract G-quadruplexes (G4s) can recruit transcription factors to activate gene expression, but detailed mechanisms remain enigmatic. Here, we demonstrate that G4s in the CCND1 promoter propel motility MAZ phase-separated condensates and subsequently transcription. Zinc finger (ZF) 2 of is a responsible for G4 binding, while ZF3-5, not highly disordered region, critical condensation. nuclear puncta overlaps with signals various coactivators including BRD4, MED1, CDK9 active RNA polymerase II, as well activation histone markers. mutants lacking either binding or phase separation ability did form puncta, showed deficiencies promoting hepatocellular carcinoma cell proliferation xenograft tumor formation. Overall, unveiled facilitate compartmentalize expression exacerbate hepatocarcinogenesis.

Язык: Английский

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DDX5 inhibits hyaline cartilage fibrosis and degradation in osteoarthritis via alternative splicing and G-quadruplex unwinding

Nature Aging, Год журнала: 2024, Номер 4(5), С. 664 - 680

Опубликована: Май 17, 2024

Abstract Hyaline cartilage fibrosis is typically considered an end-stage pathology of osteoarthritis (OA), which results in changes to the extracellular matrix. However, mechanism behind this largely unclear. Here, we found that RNA helicase DDX5 was dramatically downregulated during progression OA. deficiency increased phenotype by upregulating COL1 expression and downregulating COL2 expression. In addition, loss aggravated degradation inducing production cartilage-degrading enzymes. Chondrocyte-specific deletion Ddx5 led more severe lesions mouse OA model. Mechanistically, weakened resulted abundance Fn1 -AS-WT Plod2 transcripts, promoted fibrosis-related genes ( Col1 , Acta2 ) matrix Mmp13 Nos2 so on), respectively. Additionally, prevented unfolding Col2 promoter G-quadruplex, thereby reducing production. Together, our data suggest strategies aimed at upregulation hold significant potential for treatment

Язык: Английский

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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 Insight into Groove Binding of Yohimbine with Calf Thymus DNA: A Spectroscopic, Calorimetric, and Computational Approach

The Journal of Physical Chemistry B, Год журнала: 2023, Номер 127(22), С. 4966 - 4978

Опубликована: Май 25, 2023

A variety of anticancer and antibacterial drugs target DNA as one their primary intracellular targets. Understanding ligand–DNA interactions developing new, promising bioactive molecules for clinical use are greatly aided by elucidating the interaction between small natural polymeric DNAs. Small molecules′ ability to attach inhibit replication transcription provides more information on how impact expression genes. Yohimbine has been broadly studied in pharmacological properties, while its binding mode not explicated so far. In this study, an attempt was made explore (YH) calf thymus (CT-DNA) using varying thermodynamics silico approaches. Minor hypochromic bathochromic shifts fluorescence intensity were observed, suggesting YH CT-DNA. The Scatchard plot analysis McGhee–von Hipple method revealed noncooperative affinities range 105 M–1. stoichiometry value is 2:1 (2 span 1 base pair) determined Job's plot. thermodynamic parameters suggested exothermic binding, which favored negative enthalpy positive entropy changes from both isothermal titration calorimetry temperature-dependent experiment. Salt-dependent that ligand governed nonpolyelectrolytic forces. Kinetics experiment confirmed static type quenching. results iodide quenching, urea denaturation assay, dye displacement, melting, molecular docking (MD) groove Circular dichroism spectra minimal perturbation CT-DNA with via region. Therefore, mechanism validated biophysical techniques silico, MD findings supported here may contribute development new therapeutics possessing better efficacy lesser side effects.

Язык: Английский

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Structural investigation of pathogenic RFC1 AAGGG pentanucleotide repeats reveals a role of G-quadruplex in dysregulated gene expression in CANVAS

Nucleic Acids Research, Год журнала: 2024, Номер 52(5), С. 2698 - 2710

Опубликована: Янв. 24, 2024

Abstract An expansion of AAGGG pentanucleotide repeats in the replication factor C subunit 1 (RFC1) gene is genetic cause cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), it also links to several other neurodegenerative diseases including Parkinson's disease. However, pathogenic mechanism RFC1 repeat remains enigmatic. Here, we report that form DNA RNA parallel G-quadruplex (G4) structures play a role impairing biological processes. We determine first high-resolution nuclear magnetic resonance (NMR) structure bimolecular G4 formed by d(AAGGG)2AA reveal how fold into higher-order composed three G-tetrad layers, further demonstrate formation intramolecular G4s longer repeats. The repeats, but not nonpathogenic AAAAG stall reduce expression via translation process repeat-length-dependent manner. Our results provide an unprecedented structural basis for understanding associated with CANVAS. In addition, resolved this study will facilitate rational design small-molecule ligands helicases targeting therapeutic interventions.

Язык: Английский

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Stability and context of intercalated motifs (i-motifs) for biological applications

Biochimie, Год журнала: 2022, Номер 198, С. 33 - 47

Опубликована: Март 6, 2022

Язык: Английский

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PhpC modulates G-quadruplex-RNA landscapes in human cells

Chemical Communications, Год журнала: 2023, Номер 60(4), С. 424 - 427

Опубликована: Дек. 5, 2023

Stabilizing DNA/RNA G-quadruplexes (G4s) using small molecules (ligands) has proven an efficient strategy to decipher G4 biology. Quite paradoxically, this search also highlighted the need for finding able disrupt G4s tackle G4-associated cellular dysfunctions. We report here on both qualitative and quantitative investigations that validate G4-RNA-destabilizing properties of leading compound PhpC in human cells.

Язык: Английский

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G-quadruplexes from non-coding RNAs

Journal of Molecular Medicine, Год журнала: 2023, Номер 101(6), С. 621 - 635

Опубликована: Апрель 17, 2023

Язык: Английский

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Intelligent Biogenic Missile for Two-Photon Fluorescence Imaging-Guided Combined Photodynamic Therapy and Chemotherapy in Tumors

Analytical Chemistry, Год журнала: 2024, Номер 96(17), С. 6674 - 6682

Опубликована: Апрель 20, 2024

Photodynamic therapy (PDT) is a significant noninvasive therapeutic modality, but it often limited in its application due to the restricted tissue penetration depth caused by wavelength limitations of light source. Two-photon (TP) fluorescence techniques are capable having an excitation NIR region absorbing two photons simultaneously, which offers potential achieve higher spatial resolution for deep imaging. Thus, adoption TP affords several discernible benefits photodynamic therapy. Organic dyes possess high quantum yield. However, biocompatibility organic poor, and method coating with silica can effectively overcome limitations. Herein, based on nanoparticles, functionalized intelligent biogenic missile TP-SiNPs-G4

Язык: Английский

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