G-Quadruplex DNA as a Target in Pathogenic Bacteria: Efficacy of an Extended Naphthalene Diimide Ligand and Its Mode of Action

ABSTRACTG-quadruplexes are DNA or RNA secondary structures that can be formed from guanine-rich nucleic acids. These four-stranded structures, composed of stacked quartets of guanine bases, can be highly stable and have been demonstrated to occurin vivoin the DNA of human cells and other systems, where they play important biological roles, influencing processes such as telomere maintenance, DNA replication and transcription, or, in the case of RNA G-quadruplexes, RNA translation and processing. We report for the first time that DNA G-quadruplexes can be detected in the nuclei of the malaria parasitePlasmodium falciparum, which has one of the most A/T-biased genomes sequenced and therefore possesses few guanine-rich sequences with the potential to form G-quadruplexes. We show that despite this paucity of putative G-quadruplex-forming sequences,P. falciparumparasites are sensitive to several G-quadruplex-stabilizing drugs, including quarfloxin, which previously reached phase 2 clinical trials as an anticancer drug. Quarfloxin has a rapid initial rate of kill and is active against ring stages as well as replicative stages of intraerythrocytic development. We show that several G-quadruplex-stabilizing drugs, including quarfloxin, can suppress the transcription of a G-quadruplex-containing reporter gene inP. falciparumbut that quarfloxin does not appear to disrupt the transcription of rRNAs, which was proposed as its mode of action in both human cells and trypanosomes. These data suggest that quarfloxin has potential for repositioning as an antimalarial with a novel mode of action. Furthermore, G-quadruplex biology inP. falciparummay present a target for development of other new antimalarial drugs.

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Hybrid Imidazole-Pyridine Derivatives: An Approach to Novel Anticancer DNA Intercalators

Current Medicinal Chemistry ◽

10.2174/0929867326666181220094229 ◽

2020 ◽

Vol 27 (1) ◽

pp. 154-169 ◽

Cited By ~ 7

Author(s):

Claudiu N. Lungu ◽

Bogdan Ionel Bratanovici ◽

Maria Mirabela Grigore ◽

Vasilichia Antoci ◽

Ionel I. Mangalagiu

Keyword(s):

Experimental Data ◽

Antimicrobial Properties ◽

Qsar Model ◽

Therapeutic Effectiveness ◽

Computational Results ◽

Pyridine Derivatives ◽

Quadruplex Dna ◽

Dna Intercalators ◽

Structure Activity ◽

G Quadruplex

Lack of specificity and subsequent therapeutic effectiveness of antimicrobial and antitumoral drugs is a common difficulty in therapy. The aim of this study is to investigate, both by experimental and computational methods, the antitumoral and antimicrobial properties of a series of synthesized imidazole-pyridine derivatives. Interaction with three targets was discussed: Dickerson-Drew dodecamer (PDB id 2ADU), G-quadruplex DNA string (PDB id 2F8U) and DNA strain in complex with dioxygenase (PDB id 3S5A). Docking energies were computed and represented graphically. On them, a QSAR model was developed in order to further investigate the structure-activity relationship. Results showed that synthesized compounds have antitumoral and antimicrobial properties. Computational results agreed with the experimental data.

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Emerging Role of G-quadruplex DNA as Target in Anticancer Therapy

Current Pharmaceutical Design ◽

10.2174/1381612822666160831101031 ◽

2017 ◽

Vol 22 (44) ◽

pp. 6612-6624 ◽

Cited By ~ 35

Author(s):

Graziella Cimino-Reale ◽

Nadia Zaffaroni ◽

Marco Folini

Keyword(s):

Anticancer Therapy ◽

Quadruplex Dna ◽

G Quadruplex

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The Functional Role of Loops and Flanking Sequences of G-Quadruplex Aptamer to the Hemagglutinin of Influenza a Virus

International Journal of Molecular Sciences ◽

10.3390/ijms22052409 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2409

Author(s):

Anastasia A. Bizyaeva ◽

Dmitry A. Bunin ◽

Valeria L. Moiseenko ◽

Alexandra S. Gambaryan ◽

Sonja Balk ◽

...

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Core Structure ◽

Dna Aptamer ◽

Tertiary Structures ◽

Quadruplex Dna ◽

G Quadruplex ◽

Flanking Sequences ◽

Related Proteins

Nucleic acid aptamers are generally accepted as promising elements for the specific and high-affinity binding of various biomolecules. It has been shown for a number of aptamers that the complexes with several related proteins may possess a similar affinity. An outstanding example is the G-quadruplex DNA aptamer RHA0385, which binds to the hemagglutinins of various influenza A virus strains. These hemagglutinins have homologous tertiary structures but moderate-to-low amino acid sequence identities. Here, the experiment was inverted, targeting the same protein using a set of related, parallel G-quadruplexes. The 5′- and 3′-flanking sequences of RHA0385 were truncated to yield parallel G-quadruplex with three propeller loops that were 7, 1, and 1 nucleotides in length. Next, a set of minimal, parallel G-quadruplexes with three single-nucleotide loops was tested. These G-quadruplexes were characterized both structurally and functionally. All parallel G-quadruplexes had affinities for both recombinant hemagglutinin and influenza virions. In summary, the parallel G-quadruplex represents a minimal core structure with functional activity that binds influenza A hemagglutinin. The flanking sequences and loops represent additional features that can be used to modulate the affinity. Thus, the RHA0385–hemagglutinin complex serves as an excellent example of the hypothesis of a core structure that is decorated with additional recognizing elements capable of improving the binding properties of the aptamer.

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Assessing the Molecular Targets and Mode of Action of Furanone C-30 on Pseudomonas aeruginosa Quorum Sensing

Molecules ◽

10.3390/molecules26061620 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1620

Author(s):

Victor Markus ◽

Karina Golberg ◽

Kerem Teralı ◽

Nazmi Ozer ◽

Esti Kramarsky-Winter ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Antibiotic Resistance ◽

Quorum Sensing ◽

Conformational Changes ◽

Mode Of Action ◽

Pathogenic Bacteria ◽

Molecular Targets ◽

Resistant Bacteria ◽

Public Healthcare ◽

C 30

Quorum sensing (QS), a sophisticated system of bacterial communication that depends on population density, is employed by many pathogenic bacteria to regulate virulence. In view of the current reality of antibiotic resistance, it is expected that interfering with QS can address bacterial pathogenicity without stimulating the incidence of resistance. Thus, harnessing QS inhibitors has been considered a promising approach to overriding bacterial infections and combating antibiotic resistance that has become a major threat to public healthcare around the globe. Pseudomonas aeruginosa is one of the most frequent multidrug-resistant bacteria that utilize QS to control virulence. Many natural compounds, including furanones, have demonstrated strong inhibitory effects on several pathogens via blocking or attenuating QS. While the natural furanones show no activity against P. aeruginosa, furanone C-30, a brominated derivative of natural furanone compounds, has been reported to be a potent inhibitor of the QS system of the notorious opportunistic pathogen. In the present study, we assess the molecular targets and mode of action of furanone C-30 on P. aeruginosa QS system. Our results suggest that furanone C-30 binds to LasR at the ligand-binding site but fails to establish interactions with the residues crucial for the protein’s productive conformational changes and folding, thus rendering the protein dysfunctional. We also show that furanone C-30 inhibits RhlR, independent of LasR, suggesting a complex mechanism for the agent beyond what is known to date.

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DNA G-quadruplexes for native mass spectrometry in potassium: a database of validated structures in electrospray-compatible conditions

Nucleic Acids Research ◽

10.1093/nar/gkab039 ◽

2021 ◽

Author(s):

Anirban Ghosh ◽

Eric Largy ◽

Valérie Gabelica

Keyword(s):

Mass Spectrometry ◽

Drug Targets ◽

Native Mass Spectrometry ◽

Drug Binding ◽

Quadruplex Dna ◽

Dna Structures ◽

Nmr Structures ◽

G Quadruplex ◽

Screening Assays

Abstract G-quadruplex DNA structures have become attractive drug targets, and native mass spectrometry can provide detailed characterization of drug binding stoichiometry and affinity, potentially at high throughput. However, the G-quadruplex DNA polymorphism poses problems for interpreting ligand screening assays. In order to establish standardized MS-based screening assays, we studied 28 sequences with documented NMR structures in (usually ∼100 mM) potassium, and report here their circular dichroism (CD), melting temperature (Tm), NMR spectra and electrospray mass spectra in 1 mM KCl/100 mM trimethylammonium acetate. Based on these results, we make a short-list of sequences that adopt the same structure in the MS assay as reported by NMR, and provide recommendations on using them for MS-based assays. We also built an R-based open-source application to build and consult a database, wherein further sequences can be incorporated in the future. The application handles automatically most of the data processing, and allows generating custom figures and reports. The database is included in the g4dbr package (https://github.com/EricLarG4/g4dbr) and can be explored online (https://ericlarg4.github.io/G4_database.html).

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G-quadruplex DNA structures and their relevance in radioprotection

Biochimica et Biophysica Acta (BBA) - General Subjects ◽

10.1016/j.bbagen.2021.129857 ◽

2021 ◽

Vol 1865 (5) ◽

pp. 129857

Author(s):

Nitu Kumari ◽

Sathees C. Raghavan

Keyword(s):

Quadruplex Dna ◽

Dna Structures ◽

G Quadruplex

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Molecular Recognition and Imaging of Human Telomeric G-Quadruplex DNA in Live Cells: A Systematic Advancement of Thiazole Orange Scaffold To Enhance Binding Specificity and Inhibition of Gene Expression

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.0c01656 ◽

2021 ◽

Vol 64 (4) ◽

pp. 2125-2138

Author(s):

Wei Long ◽

Bo-Xin Zheng ◽

Xuan-He Huang ◽

Meng-Ting She ◽

Ao-Lu Liu ◽

...

Keyword(s):

Gene Expression ◽

Molecular Recognition ◽

Binding Specificity ◽

Live Cells ◽

Thiazole Orange ◽

Quadruplex Dna ◽

G Quadruplex

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G-quadruplex binding properties of a potent PARP-1 inhibitor derived from 7-azaindole-1-carboxamide

Scientific Reports ◽

10.1038/s41598-021-83474-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sabrina Dallavalle ◽

Loana Musso ◽

Roberto Artali ◽

Anna Aviñó ◽

Leonardo Scaglioni ◽

...

Keyword(s):

Therapeutic Potential ◽

Parp Inhibition ◽

Inhibition Mechanism ◽

Binding Properties ◽

Dna Oligomers ◽

Quadruplex Dna ◽

G Quadruplex ◽

Molecular Bases ◽

Dna Binding Properties ◽

Parp 1

AbstractPoly ADP-ribose polymerases (PARP) are key proteins involved in DNA repair, maintenance as well as regulation of programmed cell death. For this reason they are important therapeutic targets for cancer treatment. Recent studies have revealed a close interplay between PARP1 recruitment and G-quadruplex stabilization, showing that PARP enzymes are activated upon treatment with a G4 ligand. In this work the DNA binding properties of a PARP-1 inhibitor derived from 7-azaindole-1-carboxamide, (2-[6-(4-pyrrolidin-1-ylmethyl-phenyl)-pyrrolo[2,3-b]pyridin-1-yl]-acetamide, compound 1) with model duplex and quadruplex DNA oligomers were studied by NMR, CD, fluorescence and molecular modelling. We provide evidence that compound 1 is a strong G-quadruplex binder. In addition we provide molecular details of the interaction of compound 1 with two model G-quadruplex structures: the single repeat of human telomeres, d(TTAGGGT)4, and the c-MYC promoter Pu22 sequence. The formation of defined and strong complexes with G-quadruplex models suggests a dual G4 stabilization/PARP inhibition mechanism of action for compound 1 and provides the molecular bases of its therapeutic potential.

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