Atomistic Insights Into Interaction of Doxorubicin With DNA: From Duplex to Nucleosome

Journal of Computational Chemistry, Journal Year: 2025, Volume and Issue: 46(3)

Published: Jan. 26, 2025

ABSTRACT Doxorubicin (DOX) is a widely used chemotherapeutic agent known for intercalating into DNA. However, the exact modes of DOX interactions with various DNA structures remain unclear. Using molecular dynamics (MD) simulations, we explored duplexes (dsDNA), G‐quadruplex, and nucleosome. predominantly stacks on terminal bases dsDNA occasionally binds its minor groove. In planar tetrads but does not spontaneously intercalate these structures. Potential mean force calculations indicate that while intercalation most energetically favorable interaction mode in dsDNA, process requires overcoming significant energy barrier. contrast, intercalates bent nucleosomal DNA, due to increased torsional stress. This preferential regions higher stress provides new insights mechanism action underscores importance tertiary quaternary therapies utilizing intercalation.

Language: Английский

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A Phage‐Based Approach to Identify Antivirulence Inhibitors of Bacterial Type IV Pili

Microbial Biotechnology, Journal Year: 2025, Volume and Issue: 18(1)

Published: Jan. 1, 2025

The increasing threat of antibiotic resistance underscores the urgent need for innovative strategies to combat infectious diseases, including development antivirulants. Microbial pathogens rely on their virulence factors initiate and sustain infections. Antivirulants are small molecules designed target factors, thereby attenuating microbes. bacterial type IV pilus (T4P), an extracellular protein filament that depends T4P machinery (T4PM) its biogenesis, dynamics function, is a key factor in many significant pathogens. While T4PM presents promising antivirulence target, systematic identification inhibitors multiple constituents remains considerable challenge. Here we report novel high-throughput screening (HTS) approach discovering inhibitors. It uses Pseudomonas aeruginosa, high-priority pathogen, combination with T4P-targeting phage, φKMV. Screening library 2168 compounds using optimised protocol led tuspetinib, based deterrence lysis P. aeruginosa by Our findings show tuspetinib also inhibits two additional phages, while having no effect phage recognises lipopolysaccharides as receptor. Additionally, impedes T4P-mediated motility Acinetobacter species without impacting growth or flagellar motility. This bacterium-phage pairing applicable broad range required infection, paving ways advanced chemotherapeutics against antibiotic-resistant

Language: Английский

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Image-Based Quantitative Single-Cell Method Showed Increase of Global Chromatin Accessibility in Tumor Compared to Normal Cells

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 6, 2024

The phenotypic plasticity of cancer cells has recently emerged as an important factor treatment failure. mechanisms are not fully understood. One the hypotheses is that degree chromatin accessibility defines easiness cell transitions between different phenotypes. To test this, a method to compare overall in population or populations needed. We propose measure by fluorescence signal from nuclei stained with DNA binding fluorescent molecules. This based on observations small molecules bind nucleosome-free more easily than nucleosomal DNA. Thus, nuclear proportional amount DNA, serving accessibility. optimized using several intercalators and minor groove binders known chromatin-modulating agents demonstrated increased upon oncogene-induced transformation further tumor cells.

Language: Английский

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Epigenetics of Conjunctival Melanoma: Current Knowledge and Future Directions

Cancers, Journal Year: 2024, Volume and Issue: 16(21), P. 3687 - 3687

Published: Oct. 31, 2024

The purpose of this article is to provide a literature review the epigenetic understanding conjunctival melanoma (CM), with primary focus on current gaps in knowledge and future directions research. CM rare aggressive cancer that predominantly affects older adults. Local recurrences distant metastases commonly occur patients; however, their prediction management remain challenging. Hence, there currently an unmet need for useful biomarkers more effective treatments improve clinical outcomes these patients. Like other cancers, occurrence prognosis are believed be influenced by multiple genetic factors contribute tumor development/progression/recurrence/spread, immune evasion, primary/acquired resistance therapies. Epigenetic alterations may involve changes chromatin conformation/accessibility, post-translational histone modifications or use variants, DNA methylation, levels/functions short (small) long non-coding RNAs (ncRNAs), RNA modifications. While recent years have witnessed rapid increase available technologies modulation-based treatment options, which has enabled development/implementation various epi-drugs field, remains limited due relatively small number studies published date. These primarily investigated ncRNA (e.g., miRNA circRNA) expression, methylation. initial investigations revealed some potential and/or therapeutic targets, they had limitations, findings warrant replication independent larger studies/samples. In summary, in-depth epigenetics largely incomplete but essential advancing our molecular improving management/outcomes disease.

Language: Английский

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Chromatin remodeling with combined FACT and BET inhibition disrupts oncogenic transcription in Diffuse Midline Glioma

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 9, 2024

Abstract Aberrant epigenetic regulation is a hallmark of Diffuse Midline Glioma (DMG), an incurable pediatric brain tumor. The H3K27M driver histone mutation leads to transcriptional dysregulation, indicating that targeting the epigenome and transcription may be key therapeutic strategies against this highly aggressive cancer. One such target Facilitates Chromatin Transcription (FACT) chaperone. We found FACT enriched at developmental gene promoters, coinciding with regions open chromatin binding motifs core DMG regulatory factors. Furthermore, interacted co-localized Bromodomain Extra-Terminal Domain (BET) protein BRD4 promoters enhancers, suggesting functional cooperation between in DMG. In vitro , combinatorial approach using inhibitor CBL0137, coupled BET inhibition revealed potent synergistic cytotoxicity across range cultures, H3K27M-mutant cells demonstrating heightened sensitivity. These results were recapitulated vivo significantly extending survival three independent orthotopic PDX models Mechanistically, we show CBL0137 treatment decreased accessibility, synergizing disrupt transcription, silencing several oncogenes including MYC, PDGFRA MDM4 as well causing alterations splicing landscape. Combined, these data highlight promise simultaneously DMG, proposing novel strategy for combating devastating

Language: Английский

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Single-cell multiomics: a new frontier in drug research and development

Frontiers in Drug Discovery, Journal Year: 2024, Volume and Issue: 4

Published: Oct. 22, 2024

Single-cell multiomics (sc-multiomics) is a burgeoning field that simultaneously integrates multiple layers of molecular information, enabling the characterization dynamic cell states and activities in development disease as well treatment response. Studying drug actions responses using sc-multiomics technologies has revolutionized our understanding how small molecules intervene for specific types cancer they are linked with etiology progression. Here, we summarize recent advances have been adapted improved research development, focus on genome-wide examination drug-chromatin engagement applications response mechanisms resistance. Furthermore, discuss state-of-the-art can be taken forward to devise innovative personalized modalities biomedical research.

Language: Английский

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