A Photoresponsive Stiff‐Stilbene Ligand Fuels the Reversible Unfolding of G‐Quadruplex DNA

O’Hagan, Michael; Haldar, Susanta; Duchi, Marta; Oliver, Thomas A. A.; Mulholland, Anthony J.; Morales, Juan Carlos; Galan, M. Carmen

doi:10.1002/ange.201900740

Cited by 17 publications

(7 citation statements)

References 42 publications

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“…Over the past years, some examples of G4 unwinders have been reported, ,, such as the porphyrin TMPyP4, shown to unfold G4-DNA that folds from d[(CG 2 ) n ] trinucleotide repeats, whose expansion is involved in the Fragile X syndrome, , from the d[(G 4 C 2 ) n ] hexanucleotide repeats, whose expansion is linked to ALS/FTD, and also the thrombin binding aptamer (TBA) G4 . Other examples include an anthrathiophenedione derivative, shown to unfold the human telomeric G4-forming sequence d[(TTAGGG) n ]; the triarylpyridine TAP1, reported to disrupt the G4 that folds from a sequence of the c-kit promoter; a series of stiff-stilbenes found to regulate the folding/unfolding of the telomeric G4 in a photoresponsive manner; along with copper ion and copper complexes, , urea, , and natural polyamines (e.g., spermine) . There is, however, not broad consensus on the use of these chemicals as surrogates for helicases given that no in-depth cellular investigations have been yet performed.…”

Section: Introductionmentioning

confidence: 99%

Identifying G-Quadruplex-DNA-Disrupting Small Molecules

et al. 2021

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The quest for small molecules that strongly bind to Gquadruplex-DNA (G4), so-called G4 ligands, has invigorated the G4 research field from its very inception. Massive efforts have been invested to discover or rationally design G4 ligands, evaluate their G4interacting properties in vitro through a series of now widely accepted and routinely implemented assays, and use them as innovative chemical biology tools to interrogate cellular networks that might involve G4s. In sharp contrast, only uncoordinated efforts aimed at developing small molecules that destabilize G4s have been invested to date, even though it is now recognized that such molecular tools would have tremendous application in neurobiology as many genetic and age-related diseases are caused by an overrepresentation of G4s. Herein, we report on our efforts to develop in vitro assays to reliably identify molecules able to destabilize G4s. This workflow comprises the newly designed G4-unfold assay, adapted from the G4-helicase assay implemented with Pif1, as well as a series of biophysical and biochemical techniques classically used to study G4/ligand interactions (CD, UV−vis, PAGE, and FRET-melting), and a qPCR stop assay, adapted from a Taq-based protocol recently used to identify G4s in the genomic DNA of Schizosaccharomyces pombe. This unique, multipronged approach leads to the characterization of a phenylpyrrolocytosine (PhpC)-based G-clamp analog as a prototype of G4disrupting small molecule whose properties are validated through many different and complementary in vitro evaluations.

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Section: Introductionmentioning

confidence: 99%

Identifying G-Quadruplex-DNA-Disrupting Small Molecules

et al. 2021

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“…It was subsequently confirmed that GSH cleaving AzoDiTAB resulted in the transition of telomere DNA structures between the rigid G4 and a flexible state by breaking the interaction between DNA and AzoDiTAB. Importantly, this redox-based method for the modulation of G4 can avoid the defects of external stimulus such as light ( Wang et al., 2010 ; O'Hagan et al., 2019 ) and temperature ( Wang et al., 2015 ) in vivo application.…”

Section: Discussionmentioning

confidence: 99%

“…Among them, the photosensitive azobenzene derivative can reversibly regulate the topological structure of telomere DNA by the conversion of cis-trans state under the switching of light wavelength ( Wang et al., 2010 ) or by the supramolecular host–guest interactions under the introduction of additional substances ( Tian et al., 2017 ). Light-triggered cleavage of molecules is also an effective way to control the structure of target sequences ( O'Hagan et al., 2019 ; Wu et al., 2013 ). However, the carcinogenicity of ultraviolet light, the depth limitation of the excitation beam and complex self-assembled systems restrict the further application in cell or tissue.…”

Section: Introductionmentioning

confidence: 99%

Redox manipulation of enzyme activity through physiologically active molecule

et al. 2021

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Summary The effective utility of physiologically active molecules is crucial in numerous biological processes. However, the regulation of enzyme functions through active substances remains challenging at present. Here, glutathione (GSH), produced in cells, was used to modulate the catalytic activity of thrombin without external stimulus. It was found that high concentrations of GSH was more conducive to initiate the cleavage of compound AzoDiTAB in the range of concentration used to mimic the difference between cancer and normal cells, which has practical implications for targeting cancel cells since GSH is overexpressed in cancer cells. Importantly, GSH treatment caused the deformation of G4 structure by cleaving AzoDiTAB and thus triggered the transition of thrombin from being free to be inhibited in complex biological systems. This work would open up a new route for the specific manipulation of enzyme-catalyzed systems in cancer cells.

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“…Over the past years, some examples of G4-unwinders have been reported, [23] such as: i - the porphyrin TMPyP4, § shown to unfold G4-DNA that folds from d[(CGG) n ] trinucleotide repeats, whose expansion is involved in the Fragile X syndrome, [24] and from the d[(GGGGCC) n ] hexanucleotide repeats, whose expansion is linked to ALS/FTD; [25] ii - an anthrathiophedione derivative, shown to unfold the human telomeric G4-forming sequence d[(TTAGGG) n ]; [26] iii - the triarylpyridine TAP1, reported to disrupt the G4 that folds from a sequence of the c-kit promoter; [27] iv - a series of stiff-stilbenes found to regulate the folding/unfolding of the telomeric G4 in a photoresponsive manner; [28] along with copper ion and complexes, [29] urea [30] and natural polyamines ( e.g ., spermine). [31] There is, however, not broad consensus on the use of these chemicals as surrogates for helicases, given that no in-depth cellular investigations have been yet performed.…”

Section: Introductionmentioning

confidence: 99%

Disclosing the actual efficiency of G-quadruplex-DNA–disrupting small molecules

Mitteaux

Lejault

Pirrotta

et al. 2020

Preprint

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The quest for small molecules that avidly bind to G-quadruplex-DNA (G4-DNA, or G4), so called G4-ligands, has invigorated the G4 research field from its very inception. Massive efforts have been invested to i- screen or design G4-ligands, ii- evaluate their G4-interacting properties in vitro through a series of now widely accepted and routinely implemented assays, and iii- use them as unique chemical biology tools to interrogate cellular networks that might involve G4s. In sharp contrast, only uncoordinated efforts at developing small molecules aimed at destabilizing G4s have been invested to date, even though it is now recognized that such molecular tools would have tremendous application to neurobiology as many genetic and age-related diseases are caused by an over-representation of G4s, itself caused by a deficiency of G4-resolving enzymes, the G4-helicases. Herein, we report on our double effort to i- develop a reliable in vitro assay to identify molecules able to destabilize G4s, the G4-unfold assay, and ii- fully characterize the first prototype of G4-disrupting small molecule, a phenylpyrrolcytosine (PhpC)-based G-clamp analog.

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A Photoresponsive Stiff‐Stilbene Ligand Fuels the Reversible Unfolding of G‐Quadruplex DNA

Abstract: Scheme 1. Synthesis of the pyridinium stiff-stilbenes (E)-1 and (Z)-1.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.

Cited by 17 publications

References 42 publications

Identifying G-Quadruplex-DNA-Disrupting Small Molecules

Identifying G-Quadruplex-DNA-Disrupting Small Molecules

Redox manipulation of enzyme activity through physiologically active molecule

Disclosing the actual efficiency of G-quadruplex-DNA–disrupting small molecules

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