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5. Structural Optimization of Azacryptands for Targeting Three‐Way DNA Junctions.

Author

Pipier, Angélique, Chetot, Titouan, Kalamatianou, Apollonia, Martin, Nicolas, Caroff, Maëlle, Britton, Sébastien, Chéron, Nicolas, Trantírek, Lukáš, Granzhan, Anton, and Monchaud, David

Subjects
STRUCTURAL optimization, LIGANDS (Biochemistry), DNA, DNA damage, QUADRUPLEX nucleic acids, DNA polymerases, BASE pairs
Abstract

Transient melting of the duplex‐DNA (B‐DNA) during DNA transactions allows repeated sequences to fold into non‐B‐DNA structures, including DNA junctions and G‐quadruplexes. These noncanonical structures can act as impediments to DNA polymerase progression along the duplex, thereby triggering DNA damage and ultimately jeopardizing genomic stability. Their stabilization by ad hoc ligands is currently being explored as a putative anticancer strategy since it might represent an efficient way to inflict toxic DNA damage specifically to rapidly dividing cancer cells. The relevance of this strategy is only emerging for three‐way DNA junctions (TWJs) and, to date, no molecule has been recognized as a reference TWJ ligand, featuring both high affinity and selectivity. Herein, we characterize such reference ligands through a combination of in vitro techniques comprising affinity and selectivity assays (competitive FRET‐melting and TWJ Screen assays), functional tests (qPCR and Taq stop assays) and structural analyses (molecular dynamics and NMR investigations). We identify novel azacryptands TrisNP‐amphi and TrisNP‐ana as the most promising ligands, interacting with TWJs with high affinity and selectivity. These ligands represent new molecular tools to investigate the cellular roles of TWJs and explore how they can be exploited in innovative anticancer therapies. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Novel Synthesis of IMC-48 and Affinity Evaluation with Different i-Motif DNA Sequences

Author

Florian Berthiol, Joseph Boissieras, Hugues Bonnet, Marie Pierrot, Christian Philouze, Jean-François Poisson, Anton Granzhan, Jérôme Dejeu, and Eric Defrancq

Subjects
i-motif DNA, bio-layer interferometry, circular dichroism, affinity, IMC-48, DNA ligands, Organic chemistry, QD241-441
Abstract

During the last decade, the evidence for the biological relevance of i-motif DNA (i-DNA) has been accumulated. However, relatively few molecules were reported to interact with i-DNA, and a controversy concerning their binding mode, affinity, and selectivity persists in the literature. In this context, the cholestane derivative IMC-48 has been reported to modulate bcl-2 gene expression by stabilizing an i-motif structure in its promoter. In the present contribution, we report on a novel, more straightforward, synthesis of IMC-48 requiring fewer steps compared to the previous approach. Furthermore, the interaction of IMC-48 with four different i-motif DNA sequences was thoroughly investigated by bio-layer interferometry (BLI) and circular dichroism (CD) spectroscopy. Surprisingly, our results show that IMC-48 is a very weak ligand of i-DNA as no quantifiable interaction or significant stabilization of i-motif structures could be observed, stimulating a quest for an alternative mechanism of its biological activity.

Published
2023
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7. Novel cationic bis(acylhydrazones) as modulators of Epstein–Barr virus immune evasion acting through disruption of interaction between nucleolin and G-quadruplexes of EBNA1 mRNA

Author

Reznichenko, Oksana, Quillévéré, Alicia, Martins, Rodrigo Prado, Loaëc, Nadège, Kang, Hang, Lista, María José, Beauvineau, Claire, González-García, Jorge, Guillot, Régis, Voisset, Cécile, Daskalogianni, Chrysoula, Fåhraeus, Robin, Teulade-Fichou, Marie-Paule, Blondel, Marc, and Granzhan, Anton

Published
2019
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9. Identification of optimal fluorescent probes for G-quadruplex nucleic acids through systematic exploration of mono- and distyryl dye libraries

Author

Xiao Xie, Michela Zuffo, Marie-Paule Teulade-Fichou, and Anton Granzhan

Subjects
fluorescent probes, G-quadruplex DNA, G-quadruplex RNA, nucleic acids, styryl dyes, Science, Organic chemistry, QD241-441
Abstract

A library of 52 distyryl and 9 mono-styryl cationic dyes was synthesized and investigated with respect to their optical properties, propensity to aggregation in aqueous medium, and capacity to serve as fluorescence “light-up” probes for G-quadruplex (G4) DNA and RNA structures. Among the 61 compounds, 57 dyes showed preferential enhancement of fluorescence intensity in the presence of one or another G4-DNA or RNA structure, while no dye displayed preferential response to double-stranded DNA or single-stranded RNA analytes employed at equivalent nucleotide concentration. Thus, preferential fluorimetric response towards G4 structures appears to be a common feature of mono- and distyryl dyes, including long-known mono-styryl dyes used as mitochondrial probes or protein stains. However, the magnitude of the G4-induced “light-up” effect varies drastically, as a function of both the molecular structure of the dyes and the nature or topology of G4 analytes. Although our results do not allow to formulate comprehensive structure–properties relationships, we identified several structural motifs, such as indole- or pyrrole-substituted distyryl dyes, as well as simple mono-stryryl dyes such as DASPMI [2-(4-(dimethylamino)styryl)-1-methylpyridinium iodide] or its 4-isomer, as optimal fluorescent light-up probes characterized by high fluorimetric response (I/I0 of up to 550-fold), excellent selectivity with respect to double-stranded DNA or single-stranded RNA controls, high quantum yield in the presence of G4 analytes (up to 0.32), large Stokes shift (up to 150 nm) and, in certain cases, structural selectivity with respect to one or another G4 folding topology. These dyes can be considered as promising G4-responsive sensors for in vitro or imaging applications. As a possible application, we implemented a simple two-dye fluorimetric assay allowing rapid topological classification of G4-DNA structures.

Published
2019
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12. Alternative splicing of BCL-x is controlled by RBM25 binding to a G-quadruplex in BCL-x pre-mRNA

Author

Le Sénéchal, Ronan, primary, Keruzoré, Marc, additional, Quillévéré, Alicia, additional, Loaëc, Nadège, additional, Dinh, Van-Trang, additional, Reznichenko, Oksana, additional, Guixens-Gallardo, Pedro, additional, Corcos, Laurent, additional, Teulade-Fichou, Marie-Paule, additional, Granzhan, Anton, additional, and Blondel, Marc, additional

Published
2023
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14. Integrated high-throughput screening and large-scale isobolographic analysis to accelerate the discovery of radiosensitizers with greater selectivity for cancer cells

Author

Verrelle, Pierre, primary, Gestraud, Pierre, additional, Poyer, Florent, additional, Soria, Adèle, additional, Tessier, Sarah, additional, Lescure, Aurianne, additional, Anthony, Elodie, additional, Corbé, Maxime, additional, Henrich, Sophie, additional, Beauvineau, Claire, additional, Chaput, Ludovic, additional, Granzhan, Anton, additional, Piguel, Sandrine, additional, Perez, Franck, additional, Teulade-Fichou, Marie-Paule, additional, Megnin-Chanet, Frédérique, additional, and Nery, Elaine Del, additional

Published
2023
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18. Optimization of G‐Quadruplex Ligands through a SAR Study Combining Parallel Synthesis and Screening of Cationic Bis(acylhydrazones)

Author

Oksana Reznichenko, Denis Leclercq, Jaime Franco Pinto, Liliane Mouawad, Valérie Gabelica, Anton Granzhan, Chimie et modélisation pour la biologie du cancer (CMBC), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Européen de Chimie et Biologie (IECB), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), French Ministry of Higher Education, Research and Innovation (PhD fellowship, to OR), European Union's Horizon 2020 Framework Programme(Marie Skłodowska-Curie Grant Agreement No. 666003 through an IC-3i international PhD programme, to JFP), and benefited from access to Plateforme de BioPhysico-Chimie Structurale of the IECB (Univ. Bordeaux, CNRS UMS3033, Inserm US001) for native mass spectrometry., ANR-17-CE07-0004,DYCONAS,Chimie dynamique constitutionnelle pour les structures d'acides nucléiques(2017), GRANZHAN, Anton, and Chimie dynamique constitutionnelle pour les structures d'acides nucléiques - - DYCONAS2017 - ANR-17-CE07-0004 - AAPG2017 - VALID

Subjects
G4 ligands, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Nitrogen heterocycles, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Organic Chemistry, Combinatorial chemistry, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, General Chemistry, [CHIM.ORGA] Chemical Sciences/Organic chemistry, G-quadruplexes, N-acylhydrazones, Catalysis
Abstract

International audience; G-quadruplexes (G4s), secondary structures adopted by guanine-rich DNA and RNA sequences, are implicated in numerous biological processes and have been suggested as potential drug targets. Accordingly, there is an increasing interest in developing high-throughput methods allowing the generation of congeneric series of G4-targeting molecules (“ligands”) and investigation of their interaction with the targets. Here, we developed an operationally simple method of parallel synthesis to generate “ready-to-screen” libraries of cationic acylhydrazones, a motif that we have previously identified as a promising scaffold for potent, biologically active G4 ligands. Combined with well-established screening techniques, such as fluorescence melting, this method enables rapid synthesis and screening of combinatorial libraries of potential G4 ligands. Following this protocol, we synthesized a combinatorial library of 90 bis(acylhydrazones) and screened it against five different nucleic acid structures. This way, we were able to analyze the structure-activity relationships within this series of G4 ligands, and identified three novel promising ligands whose interaction with G4-DNA of different topologies was carefully studied by a combination of several biophysical techniques, including native mass spectrometry, and molecular modeling.

Published
2022
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20. Harnessing an emissive guanine surrogate to design small-molecule fluorescent chemosensors of O6-methylguanine-DNA-methyltransferase (MGMT)

Author

Alexandra Fillion, Jaime Franco Pinto, and Anton Granzhan

Subjects
Organic Chemistry, Physical and Theoretical Chemistry, Biochemistry
Abstract

Activity of O6-methylguanine-DNA-methyltransferase (MGMT) can be monitored in real time using chemosensors that generate an emissive guanine analogue thienoguanine (thGN).

Published
2022
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28. Dye-functionalized phosphate-binding macrocycles: from nucleotide to G-quadruplex recognition and 'turn-on' fluorescence sensing

Author

Dan Xu, Aleksandr S. Oshchepkov, Anton Granzhan, Oksana Reznichenko, Boris S. Morozov, Evgeny A. Kataev, Friedrich–Alexander University Erlangen–Nürnberg (FAU), and Chemnitz University of Technology / Technische Universität Chemnitz

Subjects
Macromolecular Substances, chemical and pharmacologic phenomena, Fluorescence sensing, 010402 general chemistry, G-quadruplex, 01 natural sciences, Catalysis, Phosphates, Turn (biochemistry), 03 medical and health sciences, chemistry.chemical_compound, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Materials Chemistry, heterocyclic compounds, Nucleotide, Fluorescent Dyes, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Molecular Structure, [CHIM.ORGA]Chemical Sciences/Organic chemistry, fungi, Metals and Alloys, DNA, General Chemistry, Phosphate, Fluorescence, Combinatorial chemistry, 0104 chemical sciences, Surfaces, Coatings and Films, Electronic, Optical and Magnetic Materials, G-Quadruplexes, Spectrometry, Fluorescence, chemistry, Ceramics and Composites
Abstract

A novel strategy to design "turn-on" fluorescent receptors for G-quadruplexes of DNA is presented, which relies on the connection of phosphate binding macrocycles (PBM) with naphthalimide dyes. A new PBM-dye family was synthesized and evaluated in terms of binding and detection of nucleotides and DNA G-quadruplexes of different topologies.

Published
2021
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29. The different activities of RNA G-quadruplex structures are controlled by flanking sequences

Author

Zheng, Alice J.-L., Thermou, Aikaterini, Gallardo, Pedro Guixens, Malbert-Colas, Laurence, Daskalogianni, Chrysoula, Vaudiau, Nathan, Brohagen, Petter, Granzhan, Anton, Blondel, Marc, Teulade-Fichou, Marie-Paule, Martins, Rodrigo Prado, Fåhraeus, Robin, Zheng, Alice J.-L., Thermou, Aikaterini, Gallardo, Pedro Guixens, Malbert-Colas, Laurence, Daskalogianni, Chrysoula, Vaudiau, Nathan, Brohagen, Petter, Granzhan, Anton, Blondel, Marc, Teulade-Fichou, Marie-Paule, Martins, Rodrigo Prado, and Fåhraeus, Robin

Abstract

The role of G-quadruplex (G4) RNA structures is multifaceted and controversial. Here, we have used as a model the EBV-encoded EBNA1 and the Kaposi's sarcoma-associated herpesvirus (KSHV)- encoded LANA1 mRNAs. We have compared the G4s in these two messages in terms of nucleolin binding, nuclear mRNA retention, and mRNA translation inhibition and their effects on immune evasion. The G4s in the EBNA1 message are clustered in one repeat sequence and the G4 ligand PhenDH2 prevents all G4-associated activities. The RNA G4s in the LANA1 message take part in similar multiple mRNA functions but are spread throughout the message. The different G4 activities depend on flanking coding and noncoding sequences and, interestingly, can be separated individually. Together, the results illustrate the multifunctional, dynamic and context-dependent nature of G4 RNAs and highlight the possibility to develop ligands targeting specific RNA G4 functions. The data also suggest a common multifunctional repertoire of viral G4 RNA activities for immune evasion.

Published
2022
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30. Assessment of presumed small-molecule ligands of telomeric i-DNA by biolayer interferometry (BLI)

Author

UCL - SST/IMCN/MOST - Molecular Chemistry, Materials and Catalysis, Bonnet, Hugues, Morel, Maéva, Devaux, Alexandre, Boissieras, Joseph, Granzhan, Anton, Elias, Benjamin, Lavergne, Thomas, Dejeu, Jérôme, Defrancq, Eric, UCL - SST/IMCN/MOST - Molecular Chemistry, Materials and Catalysis, Bonnet, Hugues, Morel, Maéva, Devaux, Alexandre, Boissieras, Joseph, Granzhan, Anton, Elias, Benjamin, Lavergne, Thomas, Dejeu, Jérôme, and Defrancq, Eric

Abstract

Biolayer interferometry (BLI) and circular dichroism (CD) spectroscopy were used to investigate the interaction between previously reported i-motif DNA (i-DNA) ligands and folded or unfolded i-DNA in acidic (pH 5.5) and near-neutral (pH 6.5) conditions. We observed that although several ligands, in particular macrocyclic bis-acridine (BisA) and pyridostatin (PDS), showed good affinities for the telomeric i-motif forming sequence, none of the ligands displayed selective interactions with the i-DNA structure nor was able to promote its formation.

Published
2022

31. Assessment of presumed small-molecule ligands of telomeric i-DNA by biolayer interferometry (BLI)

Author

Hugues Bonnet, Maéva Morel, Alexandre Devaux, Joseph Boissieras, Anton Granzhan, Benjamin Elias, Thomas Lavergne, Jérôme Dejeu, Eric Defrancq, Département de Chimie Moléculaire - Ingéniérie et Intéractions BioMoléculaires (DCM - I2BM), Département de Chimie Moléculaire (DCM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Chimie et modélisation pour la biologie du cancer (CMBC), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de la matière condensée et des nanosciences / Institute of Condensed Matter and Nanosciences (IMCN), Université Catholique de Louvain = Catholic University of Louvain (UCL), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), dejeu, jérôme, CBH-EUR-GS - - CBH-EUR-GS2017 - ANR-17-EURE-0003 - EURE - VALID, Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Technologie de Belfort-Montbeliard (UTBM)

Subjects
calculation, CD analysis, Circular Dichroism, [SDV]Life Sciences [q-bio], Metals and Alloys, DNA, Langmuir isotherm, General Chemistry, Telomere, [CHIM.COOR] Chemical Sciences/Coordination chemistry, Ligands, (Belgium) Electronic Supplementary Information (ESI) available: sensorgrams, Catalysis, Surfaces, Coatings and Films, Electronic, Optical and Magnetic Materials, Interferometry, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, experimental details, Materials Chemistry, Ceramics and Composites, [CHIM.COOR]Chemical Sciences/Coordination chemistry
Abstract

International audience; Biolayer interferometry (BLI) and circular dichroism (CD) spectroscopy were used to investigate the interaction between previously reported i-motif DNA (i-DNA) ligands and folded or unfolded i-DNA in acidic (pH 5.5) and near-neutral (pH 6.5) conditions. We observed that although several ligands, in particular macrocyclic bis-acridine (BisA) and pyridostatin (PDS), showed good affinities for the telomeric i-motif forming sequence, none of the ligands displayed selective interactions with the i-DNA structure nor was able to promote its formation.

Published
2022
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32. Quadruplex DNA-guided ligand selection from dynamic combinatorial libraries of acylhydrazones

Author

Anton Granzhan, Oksana Reznichenko, Valérie Gabelica, Anne Cucchiarini, Chimie, Modélisation et Imagerie pour la Biologie [Orsay], Université Paris-Sud - Paris 11 (UP11)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), ANR-17-CE07-0004,DYCONAS,Chimie dynamique constitutionnelle pour les structures d'acides nucléiques(2017), GRANZHAN, Anton, and Chimie dynamique constitutionnelle pour les structures d'acides nucléiques - - DYCONAS2017 - ANR-17-CE07-0004 - AAPG2017 - VALID

Subjects
010405 organic chemistry, Chemistry, Oligonucleotide, Ligand, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Organic Chemistry, Cationic polymerization, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 010402 general chemistry, Mass spectrometry, 01 natural sciences, Biochemistry, Combinatorial chemistry, 0104 chemical sciences, Catalysis, Quadruplex DNA, [CHIM.CHEM] Chemical Sciences/Cheminformatics, Titration, Physical and Theoretical Chemistry, Strong binding, [CHIM.CHEM]Chemical Sciences/Cheminformatics
Abstract

International audience; Dynamic combinatorial libraries of acylhydrazones were prepared from diacylhydrazides and several cationic or neutral aldehydes in the presence of 5-methoxyanthranilic acid catalyst. Pull-down experiments with magnetic beads functionalized with a G-quadruplex (G4)-forming oligonucleotide led to the identification of putative ligands, which were resynthesized or emulated by close structural analogues. G4-binding properties of novel derivatives were assessed by fluorimetric titrations, mass spectrometry and thermal denaturation experiments, giving evidence of strong binding (Kd < 10 nM) for two compounds.

Published
2021
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34. Harnessing intrinsic fluorescence for typing of secondary structures of DNA

Author

Anton Granzhan, Aurélie Gandolfini, Michela Zuffo, Brahim Heddi, Chimie et modélisation pour la biologie du cancer (CMBC), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biologie et pharmacologie appliquée (LBPA), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), ANR-17-CE07-0004,DYCONAS,Chimie dynamique constitutionnelle pour les structures d'acides nucléiques(2017), GRANZHAN, Anton, and Chimie dynamique constitutionnelle pour les structures d'acides nucléiques - - DYCONAS2017 - ANR-17-CE07-0004 - AAPG2017 - VALID

Subjects
[CHIM.ANAL] Chemical Sciences/Analytical chemistry, AcademicSubjects/SCI00010, Oligonucleotides, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Datasets as Topic, Biology, 010402 general chemistry, 01 natural sciences, Fluorescence, 03 medical and health sciences, chemistry.chemical_compound, Narese/14, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, [CHIM.CHEM] Chemical Sciences/Cheminformatics, Genetics, Typing, Emission spectrum, Cluster analysis, 030304 developmental biology, 0303 health sciences, Principal Component Analysis, Oligonucleotide, Discriminant Analysis, DNA, Linear discriminant analysis, 0104 chemical sciences, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, chemistry, Principal component analysis, Nucleic acid, Methods Online, Nucleic Acid Conformation, Quantum Theory, Biological system, [CHIM.CHEM]Chemical Sciences/Cheminformatics
Abstract

DNA is polymorphic since, despite its ubiquitous presence as a double-stranded helix, it is able to fold into a plethora of other secondary structures both in vitro and in cells. Despite the considerable advances that have been made in understanding this structural diversity, its high-throughput investigation still faces severe limitations. This mainly stems from the lack of suitable label-free methods, combining a fast and cheap experimental workflow with high information content. Here, we explore the use of intrinsic fluorescence emitted by nucleic acids for this scope. After a preliminary assessment of the suitability of this phenomenon for tracking the conformational changes of DNA, we examined the intrinsic steady-state emission spectra of an 89-membered set of synthetic oligonucleotides with reported conformation (G-quadruplexes, i-motifs, single- and double stranded DNA) by means of multivariate analysis. Specifically, principal component analysis of emission spectra resulted in successful clustering of oligonucleotides into three corresponding conformational groups, albeit without discrimination between single- and double-stranded structures. Linear discriminant analysis of the same training set was exploited for the assessment of new sequences, allowing the evaluation of their G4-forming propensity. Our method does not require any labelling agent or dye, avoiding the related intrinsic bias, and can be utilized to screen novel sequences of interest in a high-throughput and cost-effective manner. In addition, we observed that left-handed (Z-) G4 structures were systematically more fluorescent than most other G4 structures, almost reaching the quantum yield of 5′-d[(G3T)3G3]-3′ (G3T), the most fluorescent G4 structure reported to date. This property is likely to arise from the similar base-stacking geometry in both types of structures.

Published
2020
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37. Dual targeting of higher-order DNA structures by azacryptands induces DNA junction-mediated DNA damage in cancer cells

Author

Leïla Chouh, Anton Granzhan, Joanna Zell, David Monchaud, Nicolas Chéron, Katerina Duskova, Sébastien Britton, Madeleine Bossaert, Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC), Chimie, Modélisation et Imagerie pour la Biologie [Orsay], Université Paris-Sud - Paris 11 (UP11)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Processus d'Activation Sélective par Transfert d'Energie Uni-électronique ou Radiatif (UMR 8640) (PASTEUR), Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Monchaud, David, Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)

Subjects
AcademicSubjects/SCI00010, DNA damage, [SDV]Life Sciences [q-bio], [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Cell, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Synthetic lethality, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Chemical Biology and Nucleic Acid Chemistry, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neoplasms, Genetics, medicine, Humans, [CHIM]Chemical Sciences, 030304 developmental biology, 0303 health sciences, biology, Topoisomerase, DNA, Small molecule, In vitro, Cell biology, G-Quadruplexes, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, Cancer cell, MCF-7 Cells, biology.protein, Azabicyclo Compounds, DNA Damage
Abstract

DNA is intrinsically dynamic and folds transiently into alternative higher-order structures such as G-quadruplexes (G4s) and three-way DNA junctions (TWJs). G4s and TWJs can be stabilised by small molecules (ligands) that have high chemotherapeutic potential, either as standalone DNA damaging agents or combined in synthetic lethality strategies. While previous approaches have claimed to use ligands that specifically target either G4s or TWJs, we report here on a new approach in which ligands targeting both TWJs and G4s in vitro demonstrate cellular effects distinct from that of G4 ligands, and attributable to TWJ targeting. The DNA binding modes of these new, dual TWJ-/G4-ligands were studied by a panel of in vitro methods and theoretical simulations, and their cellular properties by extensive cell-based assays. We show here that cytotoxic activity of TWJ-/G4-ligands is mitigated by the DNA damage response (DDR) and DNA topoisomerase 2 (TOP2), making them different from typical G4-ligands, and implying a pivotal role of TWJs in cells. We designed and used a clickable ligand, TrisNP-α, to provide unique insights into the TWJ landscape in cells and its modulation upon co-treatments. This wealth of data was exploited to design an efficient synthetic lethality strategy combining dual ligands with clinically relevant DDR inhibitors., Graphical Abstract Graphical AbstractSmall molecules that concomitantly target three-way DNA junctions (TWJs) and G-quadruplexes (G4s) are used here to study the landscape of alternative DNA folds and their potential as therapeutic targets to trigger DNA structure-dependent DNA damage in human cells.

Published
2021
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38. The different activities of RNA G-quadruplex structures are controlled by flanking sequences

Author

Alice J-L Zheng, Anton Granzhan, Nathan Vaudiau, Chrysoula Daskalogianni, Robin Fåhraeus, Rodrigo Prado Martins, Aikaterini Thermou, Marc Blondel, Petter Brohagen, Marie-Paule Teulade-Fichou, Laurence Malbert-Colas, Pedro Guixens Gallardo, Hématopoïèse normale et pathologique : émergence, environnement et recherche translationnelle [Paris] ((UMR_S1131 / U1131)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), International Centre for Cancer Vaccine Science (ICCVS), Chimie et modélisation pour la biologie du cancer (CMBC), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Infectiologie et Santé Publique (UMR ISP), Université de Tours-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Masaryk Memorial Cancer Institute (RECAMO), Department of Medical Biosciences [Umeå, Suède], Umeå University, European Regional Development Fund (ENOCH)CZ.02.1.01/0.0/0.0/16_019/0000868, MH CZ-DRO (MMCI, 00209805), Cancerforskningsfonden Norr, Cancerfonden 160598, Swedish Research Council, International Centre for Cancer Vaccine Science within the International Research Agendas program of the Foundation for Polish Science, Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Masaryk Memorial Cancer Institute (MMCI), and Chanteloup, Nathalie Katy

Subjects
G4 RNA structure, Health, Toxicology and Mutagenesis, Plant Science, Computational biology, Biology, G-quadruplex, 01 natural sciences, Biochemistry, Genetics and Molecular Biology (miscellaneous), RNA Transport, 03 medical and health sciences, Immune system, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Research Articles, 030304 developmental biology, 0303 health sciences, Messenger RNA, Ecology, 010405 organic chemistry, Repertoire, Repeat sequence, Biochemistry and Molecular Biology, RNA, RNA G-quadruplex structure, 0104 chemical sciences, G-Quadruplexes, Epstein-Barr Virus Nuclear Antigens, Gene Expression Regulation, RNA, Viral, DNA, Intergenic, Nucleolin, Biokemi och molekylärbiologi, Research Article
Abstract

This study demonstrates the dynamic and multifunctional aspects of RNA G4 structures., The role of G-quadruplex (G4) RNA structures is multifaceted and controversial. Here, we have used as a model the EBV-encoded EBNA1 and the Kaposi’s sarcoma-associated herpesvirus (KSHV)-encoded LANA1 mRNAs. We have compared the G4s in these two messages in terms of nucleolin binding, nuclear mRNA retention, and mRNA translation inhibition and their effects on immune evasion. The G4s in the EBNA1 message are clustered in one repeat sequence and the G4 ligand PhenDH2 prevents all G4-associated activities. The RNA G4s in the LANA1 message take part in similar multiple mRNA functions but are spread throughout the message. The different G4 activities depend on flanking coding and non-coding sequences and, interestingly, can be separated individually. Together, the results illustrate the multifunctional, dynamic and context-dependent nature of G4 RNAs and highlight the possibility to develop ligands targeting specific RNA G4 functions. The data also suggest a common multifunctional repertoire of viral G4 RNA activities for immune evasion.

Published
2021
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39. Identification of optimal fluorescent probes for G-quadruplex nucleic acids through systematic exploration of mono- and distyryl dye libraries

Author

Marie-Paule Teulade-Fichou, Xiao Xie, Anton Granzhan, Michela Zuffo, Chimie, Modélisation et Imagerie pour la Biologie [Orsay], and Université Paris-Sud - Paris 11 (UP11)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
G-quadruplex RNA, 010402 general chemistry, G-quadruplex, 01 natural sciences, Full Research Paper, lcsh:QD241-441, chemistry.chemical_compound, symbols.namesake, lcsh:Organic chemistry, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, fluorescent probes, Stokes shift, Nucleic acid structure, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], lcsh:Science, Indole test, 010405 organic chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, RNA, styryl dyes, Fluorescence, Combinatorial chemistry, 0104 chemical sciences, Chemistry, nucleic acids, G-quadruplex DNA, chemistry, Nucleic acid, symbols, lcsh:Q, DNA
Abstract

A library of 52 distyryl and 9 mono-styryl cationic dyes was synthesized and investigated with respect to their optical properties, propensity to aggregation in aqueous medium, and capacity to serve as fluorescence “light-up” probes for G-quadruplex (G4) DNA and RNA structures. Among the 61 compounds, 57 dyes showed preferential enhancement of fluorescence intensity in the presence of one or another G4-DNA or RNA structure, while no dye displayed preferential response to double-stranded DNA or single-stranded RNA analytes employed at equivalent nucleotide concentration. Thus, preferential fluorimetric response towards G4 structures appears to be a common feature of mono- and distyryl dyes, including long-known mono-styryl dyes used as mitochondrial probes or protein stains. However, the magnitude of the G4-induced “light-up” effect varies drastically, as a function of both the molecular structure of the dyes and the nature or topology of G4 analytes. Although our results do not allow to formulate comprehensive structure–properties relationships, we identified several structural motifs, such as indole- or pyrrole-substituted distyryl dyes, as well as simple mono-stryryl dyes such as DASPMI [2-(4-(dimethylamino)styryl)-1-methylpyridinium iodide] or its 4-isomer, as optimal fluorescent light-up probes characterized by high fluorimetric response (I/I0 of up to 550-fold), excellent selectivity with respect to double-stranded DNA or single-stranded RNA controls, high quantum yield in the presence of G4 analytes (up to 0.32), large Stokes shift (up to 150 nm) and, in certain cases, structural selectivity with respect to one or another G4 folding topology. These dyes can be considered as promising G4-responsive sensors for in vitro or imaging applications. As a possible application, we implemented a simple two-dye fluorimetric assay allowing rapid topological classification of G4-DNA structures.

Published
2019
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42. Optimization of G‐Quadruplex Ligands through a SAR Study Combining Parallel Synthesis and Screening of Cationic Bis(acylhydrazones).

Author

Reznichenko, Oksana, Leclercq, Denis, Franco Pinto, Jaime, Mouawad, Liliane, Gabelica, Valérie, and Granzhan, Anton

Subjects
QUADRUPLEX nucleic acids, LIGANDS (Chemistry), STRUCTURE-activity relationships, MASS spectrometry, DRUG target, COMBINATORIAL chemistry
Abstract

G‐quadruplexes (G4s), secondary structures adopted by guanine‐rich DNA and RNA sequences, are implicated in numerous biological processes and have been suggested as potential drug targets. Accordingly, there is an increasing interest in developing high‐throughput methods that allow the generation of congeneric series of G4‐targeting molecules ("ligands") and investigating their interactions with the targets. We have developed an operationally simple method of parallel synthesis to generate "ready‐to‐screen" libraries of cationic acylhydrazones, a motif that we have previously identified as a promising scaffold for potent, biologically active G4 ligands. Combined with well‐established screening techniques, such as fluorescence melting, this method enables the rapid synthesis and screening of combinatorial libraries of potential G4 ligands. Following this protocol, we synthesized a combinatorial library of 90 bis(acylhydrazones) and screened it against five different nucleic acid structures. This way, we were able to analyze the structure–activity relationships within this series of G4 ligands, and identified three novel promising ligands whose interactions with G4‐DNAs of different topologies were studied in detail by a combination of several biophysical techniques, including native mass spectrometry, and molecular modeling. [ABSTRACT FROM AUTHOR]

Published
2023
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43. Identifying G-Quadruplex-DNA-Disrupting Small Molecules

Author

Alexandra Joubert, Pauline Lejault, Anton Granzhan, Julien Boudon, Jean-Baptiste Boulé, Jeremie Mitteaux, Filip Wojciechowski, Robert H. E. Hudson, Claude P. Gros, David Monchaud, Nicolas Desbois, Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC), University of Western Ontario (UWO), Structure et Instabilité des Génomes (STRING), Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Interdisciplinaire Carnot de Bourgogne [Dijon] (LICB), Université de Bourgogne (UB)-Université de Technologie de Belfort-Montbeliard (UTBM)-Centre National de la Recherche Scientifique (CNRS), Chimie, Modélisation et Imagerie pour la Biologie [Orsay], Université Paris-Sud - Paris 11 (UP11)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Interdisciplinaire Carnot de Bourgogne (ICB), Université de Technologie de Belfort-Montbeliard (UTBM)-Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), and Monchaud, David

Subjects
Chemical biology, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Computational biology, 010402 general chemistry, G-quadruplex, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Ligands, 01 natural sciences, Biochemistry, Catalysis, Small Molecule Libraries, 03 medical and health sciences, chemistry.chemical_compound, Colloid and Surface Chemistry, Humans, 030304 developmental biology, 0303 health sciences, biology, Molecular Structure, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, In vitro toxicology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, DNA, biology.organism_classification, [CHIM.ORGA] Chemical Sciences/Organic chemistry, Small molecule, In vitro, 0104 chemical sciences, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, G-Quadruplexes, genomic DNA, Schizosaccharomyces pombe
Abstract

International audience; 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.

Published
2021
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44. Acridine-O

Author

Jaime, Franco Pinto, Alexandra, Fillion, Patricia, Duchambon, Sophie, Bombard, and Anton, Granzhan

Subjects
Binding Sites, Guanine, Dose-Response Relationship, Drug, Molecular Structure, Tumor Suppressor Proteins, Antineoplastic Agents, DNA, Structure-Activity Relationship, DNA Repair Enzymes, Acridines, Animals, Humans, Cattle, Drug Screening Assays, Antitumor, Enzyme Inhibitors, DNA Modification Methylases, Cell Proliferation
Abstract

O

Published
2021

45. The different activities of RNA G-quadruplex structures are controlled by flanking sequences

Author

Zheng, Alice J-L, primary, Thermou, Aikaterini, additional, Guixens Gallardo, Pedro, additional, Malbert-Colas, Laurence, additional, Daskalogianni, Chrysoula, additional, Vaudiau, Nathan, additional, Brohagen, Petter, additional, Granzhan, Anton, additional, Blondel, Marc, additional, Teulade-Fichou, Marie-Paule, additional, Martins, Rodrigo Prado, additional, and Fahraeus, Robin, additional

Published
2021
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48. Quadruplex-interacting compounds for regulating the translation of the Epstein–Barr virus nuclear antigen 1 (EBNA1) mRNA: A new strategy to prevent and treat EBV-related cancers

Author

Marie-Paule Teulade-Fichou, Marc Blondel, Anton Granzhan, Robin Fåhraeus, Rodrigo Prado Martins, Chimie et modélisation pour la biologie du cancer (CMBC), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Hématopoïèse normale et pathologique : émergence, environnement et recherche translationnelle [Paris] ((UMR_S1131 / U1131)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Unité mixte de recherche de physiologie cellulaire végétale, Institut National de la Recherche Agronomique (INRA), Ligue nationale contre le cancer, La Ligue contre le Cancer-CSIRGO (2017-18), Institut National du Cancer (INCA) France (2016-169), Fondation pour la Recherche Médicale (DCM2018 1039571), Stephen Neidle, ANR-17-CE07-0004,DYCONAS,Chimie dynamique constitutionnelle pour les structures d'acides nucléiques(2017), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), GRANZHAN, Anton, Chimie dynamique constitutionnelle pour les structures d'acides nucléiques - - DYCONAS2017 - ANR-17-CE07-0004 - AAPG2017 - VALID, and Université de Tours-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, Messenger RNA, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Translation (biology), [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Biology, Virus, 3. Good health, Cell biology, 03 medical and health sciences, 0302 clinical medicine, Latent Virus, Antigen, 030220 oncology & carcinogenesis, hemic and lymphatic diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Epstein–Barr virus nuclear antigen 1, Nucleolin, Chemical genetics, 030304 developmental biology
Abstract

International audience; he Epstein–Barr (EBV) virus is linked to at least 1% of human cancers that include Burkitt's and Hodgkin's lymphomas, nasopharyngeal carcinoma, and 10% of gastric cancers. EBV is a latent virus that possesses a genome maintenance protein, EBNA1, which is both essential for the virus and highly antigenic. Hence, EBV has evolved a mechanism by which EBNA1 self-limits the translation of its own mRNA, thereby minimizing the production of EBNA1-derived antigenic peptides. Although not fully elucidated, this mechanism involves the Gly-Ala-rich (GAr) motif of EBNA1, encoded by a G-repeat-containing mRNA sequence able to form clusters of G-quadruplexes (G4s). This chapter summarizes recent significant advances in understanding this phenomenon. Mechanistic investigations based on yeast chemical genetics, cellular assays and in vitro experiments have shown that the host cell factor nucleolin (NCL) is involved in this limitation of EBNA1 translation through binding to the G4s of EBNA1 mRNA. This interaction can be disrupted by the benchmark G4-ligand PhenDC3 acting as a NCL competitor for binding to G4-RNA. Finally, exploration of the chemical space around PhenDC3 using combinatorial chemistry approach led to the generation of 20 compounds based on a bis(acylhydrazone) scaffold. Among these, two hits (PyDH2, PhenDH2) exhibit optimized properties with regard to the disruption of NCL/G4 interaction in cells, along with lower cytotoxicity. Consequently, treatment by PyDH2 or PhenDH2 increases EBNA1 production and stimulates the GAr-restricted antigenic response. Altogether, this innovative concept of antigenic stimulation sets the basis for further identification of lead candidates that may become promising candidate drugs for treating EBV-related cancers

Published
2020
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49. SARS-CoV-2 Nsp3 unique domain SUD interacts with guanine quadruplexes and G4-ligands inhibit this interaction

Author

Lavigne, Marc, Helynck, Olivier, Rigolet, Pascal, Boudria-Souilah, Rofia, Nowakowski, Mireille, Baron, Bruno, Brülé, Sébastien, Hoos, Sylviane, Raynal, Bertrand, Guittat, Lionel, Beauvineau, Claire, Petres, Stéphane, Granzhan, Anton, Guillon, Jean, Pratviel, Geneviève, Teulade-Fichou, Marie-Paule, England, Patrick, Mergny, Jean‐Louis, Munier-Lehmann, Hélène, Département de Virologie - Department of Virology, Institut Pasteur [Paris], Chimie et Biocatalyse, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Chimie et modélisation pour la biologie du cancer (CMBC), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Plateforme technologique Production et purification de protéines recombinantes – Production and Purification of Recombinant Proteins Technological Platform (PPR), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Biophysique Moléculaire (plateforme) - Molecular Biophysics (platform), Adaptateurs de signalisation en hématologie (ASIH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, Laboratoire d'Optique et Biosciences (LOB), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École polytechnique (X), Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), École polytechnique (X)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Covid Task force of the Institut Pasteur (Paris, France), ANR RA-COVID-19, internal resources of the involved laboratories originating from the Institut Pasteur, Institut Curie, and the French national research institutions (CNRS, Inserm), Université de Bordeaux, Université de Toulouse, Université Paris-Saclay, Université Sorbonne Paris-Nord, Institut Polytechnique de Paris. Funding for open access charge: ANR, RA-COVID-19., and ANR-20-COV8-0005,SUD-COVID-G4,Interaction entre le domaine SUD de SARS-CoV-2 et des quadruplex de guanines (G4), criblage de ligands de G4 aux propriétés antivirales(2020)

Subjects
Models, Molecular, AcademicSubjects/SCI00010, Protein Conformation, SARS-CoV-2, Spectrum Analysis, viruses, fungi, COVID-19, Coronavirus Papain-Like Proteases, Ligands, Virus Replication, Recombinant Proteins, G-Quadruplexes, Structure-Activity Relationship, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, RNA and RNA-protein complexes, Humans, Protein Interaction Domains and Motifs, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Protein Binding
Abstract

International audience; The multidomain non-structural protein 3 (Nsp3) is the largest protein encoded by coronavirus (CoV) genomes and several regions of this protein are essential for viral replication. Of note, SARS-CoV Nsp3 contains a SARS-Unique Domain (SUD), which can bind Guanine-rich non-canonical nucleic acid structures called G-quadruplexes (G4) and is essential for SARS-CoV replication. We show herein that the SARS-CoV-2 Nsp3 protein also contains a SUD domain that interacts with G4s. Indeed, interactions between SUD proteins and both DNA and RNA G4s were evidenced by G4 pull-down, Surface Plasmon Resonance and Homogenous Time Resolved Fluorescence. These interactions can be disrupted by mutations that prevent oligonucleotides from folding into G4 structures and, interestingly, by molecules known as specific ligands of these G4s. Structural models for these interactions are proposed and reveal significant differences with the crystallographic and modeled 3D structures of the SARS-CoV SUD-NM/G4 interaction. Altogether, our results pave the way for further studies on the role of SUD/G4 interactions during SARS-CoV-2 replication and the use of inhibitors of these interactions as potential antiviral compounds.

Published
2021
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50. Identifying G-Quadruplex-DNA-Disrupting Small Molecules

Author

Mitteaux, Jérémie, primary, Lejault, Pauline, additional, Wojciechowski, Filip, additional, Joubert, Alexandra, additional, Boudon, Julien, additional, Desbois, Nicolas, additional, Gros, Claude P., additional, Hudson, Robert H. E., additional, Boulé, Jean-Baptiste, additional, Granzhan, Anton, additional, and Monchaud, David, additional

Published
2021
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