33 results found
Weber J, Bollepalli L, Belenguer AM, et al., 2019, An Activatable Cancer-Targeted Hydrogen Peroxide Probe for Photoacoustic and Fluorescence Imaging., Cancer Res, Vol: 79, Pages: 5407-5417
Reactive oxygen species play an important role in cancer, however, their promiscuous reactivity, low abundance, and short-lived nature limit our ability to study them in real time in living subjects with conventional noninvasive imaging methods. Photoacoustic imaging is an emerging modality for in vivo visualization of molecular processes with deep tissue penetration and high spatiotemporal resolution. Here, we describe the design and synthesis of a targeted, activatable probe for photoacoustic imaging, which is responsive to one of the major and abundant reactive oxygen species, hydrogen peroxide (H2O2). This bifunctional probe, which is also detectable with fluorescence imaging, is composed of a heptamethine carbocyanine dye scaffold for signal generation, a 2-deoxyglucose cancer localization moiety, and a boronic ester functionality that specifically detects and reacts to H2O2. The optical properties of the probe were characterized using absorption, fluorescence, and photoacoustic measurements; upon addition of pathophysiologic H2O2 concentrations, a clear increase in fluorescence and red-shift of the absorption and photoacoustic spectra were observed. Studies performed in vitro showed no significant toxicity and specific uptake of the probe into the cytosol in breast cancer cell lines. Importantly, intravenous injection of the probe led to targeted uptake and accumulation in solid tumors, which enabled noninvasive photoacoustic and fluorescence imaging of H2O2. In conclusion, the reported probe shows promise for the in vivo visualization of hydrogen peroxide. SIGNIFICANCE: This study presents the first activatable and cancer-targeted hydrogen peroxide probe for photoacoustic molecular imaging, paving the way for visualization of hydrogen peroxide at high spatiotemporal resolution in living subjects.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5407/F1.large.jpg.
G-quadruplexes (G4) are alternative nucleic acid structures involved in transcription, translation and replication. Aberrant G4 formation and stabilisation is linked to genome instability and cancer. G4 ligand treatment disrupts key biological processes leading to cell death. To discover genes and pathways involved with G4s and gain mechanistic insights into G4 biology, we present the first unbiased genome-wide study to systematically identify human genes that promote cell death when silenced by shRNA in the presence of G4-stabilising small molecules. Many novel genetic vulnerabilities were revealed opening up new therapeutic possibilities in cancer, which we exemplified by an orthogonal pharmacological inhibition approach that phenocopies gene silencing. We find that targeting the WEE1 cell cycle kinase or USP1 deubiquitinase in combination with G4 ligand treatment enhances cell killing. We also identify new genes and pathways regulating or interacting with G4s and demonstrate that the DDX42 DEAD-box helicase is a newly discovered G4-binding protein.
Di Antonio M, Minard A, Liano D, et al., 2019, The unexplored potential of quinone methides in chemical biology, Bioorganic and Medicinal Chemistry, Vol: 27, Pages: 2298-2305, ISSN: 0968-0896
Quinone methides (QMs) are transient reactive species that can be efficiently generated from stable precursors under a variety of biocompatible conditions. Due to their electrophilic nature, QMs have been widely explored as cross-linking agents of DNA and proteins under physiological conditions. However, QMs also have a diene character and can irreversibly react via Diels-Alder reaction with electron-rich dienophiles. This particular reactivity has been recently exploited to label biomolecules with fluorophores in living cells.QMs are characterised by two unique properties that make them ideal candidates for chemical biology applications: i) they can be efficiently generated in situ from very stable precursors by means of bio-orthogonal protocols ii) they are reversible cross-linking agents, making them suitable for “catch and release” target-enrichment experiments. Nevertheless, there are only few examples reported to date that truly take advantage of QMs unique chemistry in the context of chemical-biology assay development. In this review, we will examine the most relevant examples that illustrate the benefit of using QMs for chemical biology purposes and we will anticipate novel approaches to further their applications in biologically relevant contexts.
Sengar A, Vandana JJ, Chambers VS, et al., 2019, Structure of a (3+1) hybrid G-quadruplex in the PARP1 promoter., Nucleic Acids Res, Vol: 47, Pages: 1564-1572
Poly (ADP-ribose) polymerase 1 (PARP1) has emerged as an attractive target for cancer therapy due to its key role in DNA repair processes. Inhibition of PARP1 in BRCA-mutated cancers has been observed to be clinically beneficial. Recent genome-mapping experiments have identified a non-canonical G-quadruplex-forming sequence containing bulges within the PARP1 promoter. Structural features, like bulges, provide opportunities for selective chemical targeting of the non-canonical G-quadruplex structure within the PARP1 promoter, which could serve as an alternative therapeutic approach for the regulation of PARP1 expression. Here we report the G-quadruplex structure formed by a 23-nucleotide G-rich sequence in the PARP1 promoter. Our study revealed a three-layered intramolecular (3+1) hybrid G-quadruplex scaffold, in which three strands are oriented in one direction and the fourth in the opposite direction. This structure exhibits unique structural features such as an adenine bulge and a G·G·T base triple capping structure formed between the central edgewise loop, propeller loop and 5' flanking terminal. Given the highly important role of PARP1 in DNA repair and cancer intervention, this structure presents an attractive opportunity to explore the therapeutic potential of PARP1 inhibition via G-quadruplex DNA targeting.
Mao S-Q, Ghanbarian AT, Spiegel J, et al., 2018, DNA G-quadruplex structures mold the DNA methylome., Nat Struct Mol Biol, Vol: 25, Pages: 951-957
Control of DNA methylation level is critical for gene regulation, and the factors that govern hypomethylation at CpG islands (CGIs) are still being uncovered. Here, we provide evidence that G-quadruplex (G4) DNA secondary structures are genomic features that influence methylation at CGIs. We show that the presence of G4 structure is tightly associated with CGI hypomethylation in the human genome. Surprisingly, we find that these G4 sites are enriched for DNA methyltransferase 1 (DNMT1) occupancy, which is consistent with our biophysical observations that DNMT1 exhibits higher binding affinity for G4s as compared to duplex, hemi-methylated, or single-stranded DNA. The biochemical assays also show that the G4 structure itself, rather than sequence, inhibits DNMT1 enzymatic activity. Based on these data, we propose that G4 formation sequesters DNMT1 thereby protecting certain CGIs from methylation and inhibiting local methylation.
Greenfield JL, Evans EW, Di Nuzzo D, et al., 2018, Unraveling Mechanisms of Chiral Induction in Double-Helical Metallopolymers, Journal of the American Chemical Society, Vol: 140, Pages: 10344-10353, ISSN: 0002-7863
© 2018 American Chemical Society. Self-assembled helical polymers hold great promise as new functional materials, where helical handedness controls useful properties such as circularly polarized light emission or electron spin. The technique of subcomponent self-assembly can generate helical polymers from readily prepared monomers. Here we present three distinct strategies for chiral induction in double-helical metallopolymers prepared via subcomponent self-assembly: (1) employing an enantiopure monomer, (2) polymerization in a chiral solvent, (3) using an enantiopure initiating group. Kinetic and thermodynamic models were developed to describe the polymer growth mechanisms and quantify the strength of chiral induction, respectively. We found the degree of chiral induction to vary as a function of polymer length. Ordered, rod-like aggregates more than 70 nm long were also observed in the solid state. Our findings provide a basis to choose the most suitable method of chiral induction based on length, regiochemical, and stereochemical requirements, allowing stereochemical control to be established in easily accessible ways.
Sahakyan AB, Chambers VS, Marsico G, et al., 2017, Machine learning model for sequence-driven DNA G-quadruplex formation, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
Hansel-Hertsch R, Di Antonio M, Balasubramanian S, 2017, DNA G-quadruplexes in the human genome: detection, functions and therapeutic potential, NATURE REVIEWS MOLECULAR CELL BIOLOGY, Vol: 18, Pages: 279-284, ISSN: 1471-0072
Nieto-Orellana A, Di Antonio M, Conte C, et al., 2017, Effect of polymer topology on non-covalent polymer-protein complexation: miktoarm versus linear mPEG-poly(glutamic acid) copolymers, POLYMER CHEMISTRY, Vol: 8, Pages: 2210-2220, ISSN: 1759-9954
Xu H, Di Antonio M, McKinney S, et al., 2017, CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours, NATURE COMMUNICATIONS, Vol: 8, ISSN: 2041-1723
Nicoli F, Roos MK, Hemmig EA, et al., 2016, Proximity-Induced H-Aggregation of Cyanine Dyes on DNA-Duplexes, JOURNAL OF PHYSICAL CHEMISTRY A, Vol: 120, Pages: 9941-9947, ISSN: 1089-5639
Hansel-Hertsch R, Beraldi D, Lensing SV, et al., 2016, G-quadruplex structures mark human regulatory chromatin, NATURE GENETICS, Vol: 48, Pages: 1267-1272, ISSN: 1061-4036
Chambers VS, Marsico G, Boutell JM, et al., 2015, High-throughput sequencing of DNA G-quadruplex structures in the human genome, NATURE BIOTECHNOLOGY, Vol: 33, Pages: 877-+, ISSN: 1087-0156
Yangyuoru PM, Di Antonio M, Ghimire C, et al., 2015, Dual Binding of an Antibody and a Small Molecule Increases the Stability of TERRA G-Quadruplex, ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, Vol: 54, Pages: 910-913, ISSN: 1433-7851
Yangyuoru PM, DiAntonio M, Ghimire C, et al., 2015, Dual Binding of an Antibody and a Small Molecule Increases the Stability of TERRA G-Quadruplex, Angewandte Chemie, Vol: 127, Pages: 924-927, ISSN: 0044-8249
Le DD, Di Antonio M, Chan LKM, et al., 2015, G-quadruplex ligands exhibit differential G-tetrad selectivity, CHEMICAL COMMUNICATIONS, Vol: 51, Pages: 8048-8050, ISSN: 1359-7345
Di Antonio M, McLuckie KIE, Balasubramanian S, 2014, Reprogramming the Mechanism of Action of Chlorambucil by Coupling to a G-Quadruplex Ligand, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol: 136, Pages: 5860-5863, ISSN: 0002-7863
Biffi G, Di Antonio M, Tannahill D, et al., 2014, Visualization and selective chemical targeting of RNA G-quadruplex structures in the cytoplasm of human cells, NATURE CHEMISTRY, Vol: 6, Pages: 75-80, ISSN: 1755-4330
Di Antonio M, 2014, Quinone Methides Generation: Applications in Chemical Biology, CURRENT ORGANIC CHEMISTRY, Vol: 18, Pages: 2-2, ISSN: 1385-2728
McLuckie KIE, Di Antonio M, Zecchini H, et al., 2013, G-Quadruplex DNA as a Molecular Target for Induced Synthetic Lethality in Cancer Cells, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol: 135, Pages: 9640-9643, ISSN: 0002-7863
Mitchell T, Ramos-Montoya A, Di Antonio M, et al., 2013, Downregulation of Androgen Receptor Transcription by Promoter G-Quadruplex Stabilization as a Potential Alternative Treatment for Castrate-Resistant Prostate Cancer, BIOCHEMISTRY, Vol: 52, Pages: 1429-1436, ISSN: 0006-2960
Nikan M, Di Antonio M, Abecassis K, et al., 2013, An Acetylene-Bridged 6,8-Purine Dimer as a Fluorescent Switch-On Probe for Parallel G-Quadruplexes, ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, Vol: 52, Pages: 1428-1431, ISSN: 1433-7851
Murat P, Gormally MV, Sanders D, et al., 2013, Light-mediated in cell downregulation of G-quadruplex-containing genes using a photo-caged ligand, CHEMICAL COMMUNICATIONS, Vol: 49, Pages: 8453-8455, ISSN: 1359-7345
Di Antonio M, Rodriguez R, Balasubramanian S, 2012, Experimental approaches to identify cellular G-quadruplex structures and functions, METHODS, Vol: 57, Pages: 84-92, ISSN: 1046-2023
Di Antonio M, Biffi G, Mariani A, et al., 2012, Selective RNA Versus DNA G-Quadruplex Targeting by In Situ Click Chemistry, ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, Vol: 51, Pages: 11073-11078, ISSN: 1433-7851
Doria F, Nadai M, Folini M, et al., 2012, Hybrid ligand-alkylating agents targeting telomeric G-quadruplex structures, ORGANIC & BIOMOLECULAR CHEMISTRY, Vol: 10, Pages: 2798-2806, ISSN: 1477-0520
Mueller S, Sanders DA, Di Antonio M, et al., 2012, Pyridostatin analogues promote telomere dysfunction and long-term growth inhibition in human cancer cells, ORGANIC & BIOMOLECULAR CHEMISTRY, Vol: 10, Pages: 6537-6546, ISSN: 1477-0520
Nadai M, Doria F, Di Antonio M, et al., 2011, Naphthalene diimide scaffolds with dual reversible and covalent interaction properties towards G-quadruplex, BIOCHIMIE, Vol: 93, Pages: 1328-1340, ISSN: 0300-9084
Percivalle C, La Rosa A, Verga D, et al., 2011, Quinone Methide Generation via Photoinduced Electron Transfer, JOURNAL OF ORGANIC CHEMISTRY, Vol: 76, Pages: 3096-3106, ISSN: 0022-3263
Verga D, Nadai M, Doria F, et al., 2010, Photogeneration and Reactivity of Naphthoquinone Methides as Purine Selective DNA Alkylating Agents, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol: 132, Pages: 14625-14637, ISSN: 0002-7863
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