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Chemistry and Biology of Noncanonical Nucleic Acid Structures: From Physicochemical Properties to Therapeutic Applications

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 11155

Special Issue Editors

Department of Pharmacy, Universita degli Studi di Napoli Federico II, 80131 Naples, Italy
Interests: DNA; proteins; medicinal and pharmaceutical chemistry; fluorescence; DSC; biophysics; aptamers
Department of Pharmacy, School of Medicine and Surgery, Università degli Studi di Napoli Federico II, 80131 Naples, Italy
Interests: noncanonical nucleic acids; structural biology
Special Issues, Collections and Topics in MDPI journals
Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy
Interests: chemistry of nucleic acids; nucleic acids therapeutics; nucleic acid-targeting drugs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Nucleic acids have the ability to form several different hydrogen bonding patterns. This enables them to attain a variety of structural and conformational polymorphic forms. Indeed, nucleic acids can exist in single-stranded form or fold into secondary structures, which include the canonical double helix as well as noncanonical structures such as the G-quadruplex and i-motif species. Noncanonical structures in turn encompass an ensemble of conformers depending on the sequence composition and/or environmental conditions.

In vivo, such noncanonical nucleic acid structures may form in important genomic regions and have key roles in several biological processes, including the modulation of oncogenes expression, and therefore represent potential anticancer drug targets. In addition, conformational equilibria of noncanonical structures may be finely modulated by specific proteins that recognize a given form.

Many nucleic acid aptamers, which typically have defined structures owing to their propensity to form certain base pairs, also fold into noncanonical structures, thus forming unique three-dimensional structures that are capable of specific molecular recognition of their cognate targets.

Furthermore, the nanoscale geometry and dynamic properties of noncanonical nucleic acid structures, along with their inherent biocompatibility and biodegradability, have made such structural motifs promising candidates for the development of functional nanostructures and nanodevices.

In this Special Issue, we aim to cover important and new aspects concerning the chemistry and biology of noncanonical nucleic acid structures, with emphasis on their structure, stability, conformational equilibria, as well as on the biological relevance of their interactions with proteins and drugs. We welcome contributions that involve biophysical, biochemical, molecular biology, as well as computational approaches to the analysis of these systems. Studies concerning functional noncanonical nucleic acids with potential applications in therapy, diagnostics, and analytics are also welcome.

This Special Issue welcomes original research articles, review, and commentaries that focus on but are not limited to the above topics.

Prof. Dr. Bruno Pagano
Prof. Dr. Antonio Randazzo
Prof. Dr. Jussara Amato
Guest Editors

Manuscript Submission Information

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Keywords

  • noncanonical nucleic acid structures
  • noncanonical nucleic acid-targeting ligands
  • biophysical studies of noncanonical nucleic acids
  • thermodynamics and kinetics of noncanonical nucleic acid structures
  • structure–function relationship of noncanonical nucleic acids
  • noncanonical nucleic acid–protein interactions
  • functional nucleic acids
  • aptamers
  • biological roles of noncanonical nucleic acids
  • noncanonical nucleic acids-related diseases

Published Papers (5 papers)

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Research

27 pages, 8686 KiB  
Article
Selective Targeting of Cancer-Related G-Quadruplex Structures by the Natural Compound Dicentrine
Int. J. Mol. Sci. 2023, 24(4), 4070; https://doi.org/10.3390/ijms24044070 - 17 Feb 2023
Cited by 5 | Viewed by 1599
Abstract
Aiming to identify highly effective and selective G-quadruplex ligands as anticancer candidates, five natural compounds were investigated here, i.e., the alkaloids Canadine, D-Glaucine and Dicentrine, as well as the flavonoids Deguelin and Millettone, selected as analogs of compounds previously identified as promising G-quadruplex-targeting [...] Read more.
Aiming to identify highly effective and selective G-quadruplex ligands as anticancer candidates, five natural compounds were investigated here, i.e., the alkaloids Canadine, D-Glaucine and Dicentrine, as well as the flavonoids Deguelin and Millettone, selected as analogs of compounds previously identified as promising G-quadruplex-targeting ligands. A preliminary screening with the G-quadruplex on the Controlled Pore Glass assay proved that, among the investigated compounds, Dicentrine is the most effective ligand of telomeric and oncogenic G-quadruplexes, also showing good G-quadruplex vs. duplex selectivity. In-depth studies in solution demonstrated the ability of Dicentrine to thermally stabilize telomeric and oncogenic G-quadruplexes without affecting the control duplex. Interestingly, it showed higher affinity for the investigated G-quadruplex structures over the control duplex (Kb~106 vs. 105 M−1), with some preference for the telomeric over the oncogenic G-quadruplex model. Molecular dynamics simulations indicated that Dicentrine preferentially binds the G-quadruplex groove or the outer G-tetrad for the telomeric and oncogenic G-quadruplexes, respectively. Finally, biological assays proved that Dicentrine is highly effective in promoting potent and selective anticancer activity by inducing cell cycle arrest through apoptosis, preferentially targeting G-quadruplex structures localized at telomeres. Taken together, these data validate Dicentrine as a putative anticancer candidate drug selectively targeting cancer-related G-quadruplex structures. Full article
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20 pages, 4543 KiB  
Article
Detection of SARS-CoV-2 Virus by Triplex Enhanced Nucleic Acid Detection Assay (TENADA)
Int. J. Mol. Sci. 2022, 23(23), 15258; https://doi.org/10.3390/ijms232315258 - 03 Dec 2022
Cited by 2 | Viewed by 3805
Abstract
SARS-CoV-2, a positive-strand RNA virus has caused devastating effects. The standard method for COVID diagnosis is based on polymerase chain reaction (PCR). The method needs expensive reagents and equipment and well-trained personnel and takes a few hours to be completed. The search for [...] Read more.
SARS-CoV-2, a positive-strand RNA virus has caused devastating effects. The standard method for COVID diagnosis is based on polymerase chain reaction (PCR). The method needs expensive reagents and equipment and well-trained personnel and takes a few hours to be completed. The search for faster solutions has led to the development of immunological assays based on antibodies that recognize the viral proteins that are faster and do not require any special equipment. Here, we explore an innovative analytical approach based on the sandwich oligonucleotide hybridization which can be adapted to several biosensing devices including thermal lateral flow and electrochemical devices, as well as fluorescent microarrays. Polypurine reverse-Hoogsteen hairpins (PPRHs) oligonucleotides that form high-affinity triplexes with the polypyrimidine target sequences are used for the efficient capture of the viral genome. Then, a second labeled oligonucleotide is used to detect the formation of a trimolecular complex in a similar way to antigen tests. The reached limit of detection is around 0.01 nM (a few femtomoles) without the use of any amplification steps. The triplex enhanced nucleic acid detection assay (TENADA) can be readily adapted for the detection of any pathogen requiring only the knowledge of the pathogen genome sequence. Full article
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9 pages, 1906 KiB  
Article
The Promoter Region of the Proto-Oncogene MST1R Contains the Main Features of G-Quadruplexes Formation
Int. J. Mol. Sci. 2022, 23(21), 12905; https://doi.org/10.3390/ijms232112905 - 26 Oct 2022
Cited by 3 | Viewed by 1225
Abstract
MST1R (RON) is a receptor of the MET tyrosine kinase receptor family involved in several cancers such as pancreas, breast, ovary, colon, and stomach. Some studies have shown that overexpression of MST1R increases the migratory and invasive properties of cancer cells. The promoter [...] Read more.
MST1R (RON) is a receptor of the MET tyrosine kinase receptor family involved in several cancers such as pancreas, breast, ovary, colon, and stomach. Some studies have shown that overexpression of MST1R increases the migratory and invasive properties of cancer cells. The promoter region of the oncogene MST1R is enriched in guanine residues that can potentially form G-quadruplexes (G4s), as it was observed in other oncogenic promoters such as KRAS and c-MYC. There is abundant literature that links the presence of G4s in promoter regions of oncogenes to diverse gene regulation processes that are not well understood. In this work, we have studied the reverse and forward sequence of MST1R promoter region using the G4Hunter software and performed biophysical studies to characterize the best scored sequences. Full article
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13 pages, 2326 KiB  
Article
Solvent Vibrations as a Proxy of the Telomere G-Quadruplex Rearrangements across Thermal Unfolding
Int. J. Mol. Sci. 2022, 23(9), 5123; https://doi.org/10.3390/ijms23095123 - 04 May 2022
Cited by 4 | Viewed by 1625
Abstract
G-quadruplexes (G4s) are noncanonical forms of DNA involved in many key genome functions. Here, we exploited UV Resonance Raman scattering to simultaneously explore the vibrational behavior of a human telomeric G4 (Tel22) and its aqueous solvent as the biomolecule underwent thermal melting. We [...] Read more.
G-quadruplexes (G4s) are noncanonical forms of DNA involved in many key genome functions. Here, we exploited UV Resonance Raman scattering to simultaneously explore the vibrational behavior of a human telomeric G4 (Tel22) and its aqueous solvent as the biomolecule underwent thermal melting. We found that the OH stretching band, related to the local hydrogen-bonded network of a water molecule, was in strict relation with the vibrational features of the G4 structure as a function of temperature. In particular, the modifications to the tetrahedral ordering of the water network were strongly coupled to the DNA rearrangements, showing changes in temperature that mirrored the multi-step melting process of Tel22. The comparison between circular dichroism and Raman results supported this view. The present findings provide novel insights into the impact of the molecular environment on G4 conformation. Improving current knowledge on the solvent structural properties will also contribute to a better understanding of the role played by water arrangement in the complexation of G4s with ligands. Full article
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18 pages, 3705 KiB  
Article
Fighting the Huntington’s Disease with a G-Quadruplex-Forming Aptamer Specifically Binding to Mutant Huntingtin Protein: Biophysical Characterization, In Vitro and In Vivo Studies
Int. J. Mol. Sci. 2022, 23(9), 4804; https://doi.org/10.3390/ijms23094804 - 27 Apr 2022
Cited by 5 | Viewed by 2026
Abstract
A set of guanine-rich aptamers able to preferentially recognize full-length huntingtin with an expanded polyglutamine tract has been recently identified, showing high efficacy in modulating the functions of the mutated protein in a variety of cell experiments. We here report a detailed biophysical [...] Read more.
A set of guanine-rich aptamers able to preferentially recognize full-length huntingtin with an expanded polyglutamine tract has been recently identified, showing high efficacy in modulating the functions of the mutated protein in a variety of cell experiments. We here report a detailed biophysical characterization of the best aptamer in the series, named MS3, proved to adopt a stable, parallel G-quadruplex structure and show high nuclease resistance in serum. Confocal microscopy experiments on HeLa and SH-SY5Y cells, as models of non-neuronal and neuronal cells, respectively, showed a rapid, dose-dependent uptake of fluorescein-labelled MS3, demonstrating its effective internalization, even in the absence of transfecting agents, with no general cytotoxicity. Then, using a well-established Drosophila melanogaster model for Huntington’s disease, which expresses the mutated form of human huntingtin, a significant improvement in the motor neuronal function in flies fed with MS3 was observed, proving the in vivo efficacy of this aptamer. Full article
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