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G-Quadruplexes and Their Ligands: Biophysical Methods to Unravel G-Quadruplex/Ligand Interactions.

ABSTRACT: Progress in the design of G-quadruplex (G4) binding ligands relies on the availability of approaches that assess the binding mode and nature of the interactions between G4 forming sequences and their putative ligands. The experimental approaches used to characterize G4/ligand interactions can be categorized into structure-based methods (circular dichroism (CD), nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography), affinity and apparent affinity-based methods (surface plasmon resonance (SPR), isothermal titration calorimetry (ITC) and mass spectrometry (MS)), and high-throughput methods (fluorescence resonance energy transfer (FRET)-melting, G4-fluorescent intercalator displacement assay (G4-FID), affinity chromatography and microarrays. Each method has unique advantages and drawbacks, which makes it essential to select the ideal strategies for the biological question being addressed. The structural- and affinity and apparent affinity-based methods are in several cases complex and/or time-consuming and can be combined with fast and cheap high-throughput approaches to improve the design and development of new potential G4 ligands. In recent years, the joint use of these techniques permitted the discovery of a huge number of G4 ligands investigated for diagnostic and therapeutic purposes. Overall, this review article highlights in detail the most commonly used approaches to characterize the G4/ligand interactions, as well as the applications and types of information that can be obtained from the use of each technique.

SUBMITTER: Santos T

PROVIDER: S-EPMC8401999 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Human enteroviruses cause many diseases; however, there is no specific therapeutic drug. G-quadruplex is an atypical secondary structure formed in the guanine rich region of DNA or RNA, which can exist in the viral genome. The different positions of G-quadruplex play an important role in the regulation of virus replication and infection. Whether G-quadruplexes are present in human enteroviruses is unknown. In current study, we analyzed the potential quadruplex forming sequences of human enteroviruses, especially EV-A71 virus, which causes hand, foot, and mouth disease. The results showed that there were a certain number of potential quadruplex-forming sequences in human enteroviruses. Through a variety of experimental methods, we evaluated the formation potential of EV-A71 encoded G-quadruplex and analyzed the binding ability of G-quadruplex ligands, including BRACO-19, pyridostatin and TMPyP4 to virus encoded G-quadruplexes. G-quadruplex ligands BRACO-19, PDS and TMPyP4 could inhibit the transcription of constructs containing EV-A71 G-quadruplex sequences. Moreover, we found that BRACO-19 was able to inhibit the replication of EV-A71, suggesting that targeting G-quadruplexes in EV-A71 genome by G-quadruplex ligands could be a novel antiviral way against EV-A71. Our finding not only uncovered the G-quadruplexes in human enteroviruses, but also would provide a new strategy for human enteroviruses therapy. IMPORTANCE G-quadruplex is a stable nucleic acid secondary structure formed by the folding of guanine rich nucleic acid. The important regulatory function of G-quadruplex makes it an attractive target of antiviral effect. Human enteroviruses cause a variety of human diseases, including common cold, nervous system diseases, cardiovascular damage, and diabetes. Enterovirus A71 (EV-A71) is one of pathogens causing hand, foot, and mouth disease; however, whether G-quadruplexes are present in the genomes of human enteroviruses is unknown. The function of G-quadruplexes in the EV-A71 genomes is not clear. We predicted and characterized G-quadruplex sequences in EV-A71. G-quadruplex ligands were identified to stabilize EV-A71 G-quadruplexes with high affinities. We also demonstrated G-quadruplex ligand BRACO-19 inhibited EV-A71 replication. Our studies provide a framework for targeting G-quadruplexes in the enteroviruses genome, which will be a new way to develop antiviral agents against human enteroviruses.

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G-Quadruplexes and Their Ligands: Biophysical Methods to Unravel G-Quadruplex/Ligand Interactions.

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