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Special Issue "Peptide Nucleic Acids: Applications in Biomedical Sciences"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 19368

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Special Issue Editor

Prof. Dr. Eylon Yavin
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Guest Editor
Head, Drug Research teaching programHead, Department of Medicinal ChemistryPresident of the Medicinal Chemistry Section of the Israel Chemical SocietyThe School of Pharmacy, The Faculty of Medicine, The Hebrew University of Jerusalem, Hadassah Ein Kerem, Jerusalem 91120, Israel
Interests: PNA; splice switching oligonucleotides; FIT-(Forced Intercalation)-PNA; cancer diagnosis; SNP detection; PNA-peptide conjugates
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Special Issue Information

Dear Colleagues,

Peptide Nucleic Acid (PNA) is a purely synthetic DNA analogue that has been used in the last three decades for a variety of biomedical applications. PNA consists of a pseudo-peptide backbone from which one of each of the possible four canonical bases (A, G, C, and T) is introduced in a way that allows highly efficient hybridization to complementary RNA or DNA sequences. PNA oligomers have several properties that make them suitable for use in the field of biology/medicine including (1) high stability in biological fluids, and (2) cell permeability by conjugation of PNA to a CPP (cell penetrating peptide), lipid, or ligand, and/or encapsulation into nano/micro particles.

As therapeutic molecules, PNAs have been developed as potent and specific antiviral and antimicrobial agents. In addition, they have been used to effect splicing events as a means of treating genetic disorders (e.g., Duchene Muscular Dystrophy). In addition, modified PNAs (e.g., gamma-PNAs) have been shown to act as potent antigene molecules (targeting dsDNA as well as dsRNA). In the diagnostic field, PNAs have been used to detect a variety of RNA biomarkers in living cells associated with diseases (e.g., cancer) and were also designed to detect single point mutations associated with certain diseases.

This Special Issue is intended to provide a platform to report advances and challenges in both the therapeutic and diagnostic fields associated with PNA chemistry. Specifically, perspectives related to PNA cellular uptake, bio-availability, specificity, sensitivity, and potency are welcomed, as are focused review articles by experts in the PNA field.

Prof. Eylon Yavin
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2300 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • PNA
  • antisense
  • antigene
  • RNA/DNA diagnosis
  • antiviral PNA
  • antimicrobial PNA
  • chemically modified PNA
  • strand invasion

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Published Papers (9 papers)

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Editorial

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Editorial
Peptide Nucleic Acids: Applications in Biomedical Sciences
Molecules 2020, 25(15), 3317; https://doi.org/10.3390/molecules25153317 - 22 Jul 2020
Cited by 3 | Viewed by 859
Abstract
The DNA mimic, PNA (peptide nucleic acid), has been with us now for almost 3 decades [...] Full article
(This article belongs to the Special Issue Peptide Nucleic Acids: Applications in Biomedical Sciences)
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Research

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Article
l-DNA-Based Catalytic Hairpin Assembly Circuit
Molecules 2020, 25(4), 947; https://doi.org/10.3390/molecules25040947 - 20 Feb 2020
Cited by 11 | Viewed by 1925
Abstract
Isothermal, enzyme-free amplification methods based on DNA strand-displacement reactions show great promise for applications in biosensing and disease diagnostics but operating such systems within biological environments remains extremely challenging due to the susceptibility of DNA to nuclease degradation. Here, we report a catalytic [...] Read more.
Isothermal, enzyme-free amplification methods based on DNA strand-displacement reactions show great promise for applications in biosensing and disease diagnostics but operating such systems within biological environments remains extremely challenging due to the susceptibility of DNA to nuclease degradation. Here, we report a catalytic hairpin assembly (CHA) circuit constructed from nuclease-resistant l-DNA that is capable of unimpeded signal amplification in the presence of 10% fetal bovine serum (FBS). The superior biostability of the l-DNA CHA circuit relative to its native d-DNA counterpart was clearly demonstrated through a direct comparison of the two systems (d versus l) under various conditions. Importantly, we show that the l-CHA circuit can be sequence-specifically interfaced with an endogenous d-nucleic acid biomarker via an achiral peptide nucleic acid (PNA) intermediary, enabling catalytic detection of the target in FBS. Overall, this work establishes a blueprint for the detection of low-abundance nucleic acids in harsh biological environments and provides further impetus for the construction of DNA nanotechnology using l-oligonucleotides. Full article
(This article belongs to the Special Issue Peptide Nucleic Acids: Applications in Biomedical Sciences)
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Article
SNP Discrimination by Tolane-Modified Peptide Nucleic Acids: Application for the Detection of Drug Resistance in Pathogens
Molecules 2020, 25(4), 769; https://doi.org/10.3390/molecules25040769 - 11 Feb 2020
Cited by 2 | Viewed by 1705
Abstract
During the treatment of viral or bacterial infections, it is important to evaluate any resistance to the therapeutic agents used. An amino acid substitution arising from a single base mutation in a particular gene often causes drug resistance in pathogens. Therefore, molecular tools [...] Read more.
During the treatment of viral or bacterial infections, it is important to evaluate any resistance to the therapeutic agents used. An amino acid substitution arising from a single base mutation in a particular gene often causes drug resistance in pathogens. Therefore, molecular tools that discriminate a single base mismatch in the target sequence are required for achieving therapeutic success. Here, we synthesized peptide nucleic acids (PNAs) derivatized with tolane via an amide linkage at the N-terminus and succeeded in improving the sequence specificity, even with a mismatched base pair located near the terminal region of the duplex. We assessed the sequence specificities of the tolane-PNAs for single-strand DNA and RNA by UV-melting temperature analysis, thermodynamic analysis, an in silico conformational search, and a gel mobility shift assay. As a result, all of the PNA-tolane derivatives stabilized duplex formation to the matched target sequence without inducing mismatch target binding. Among the different PNA-tolane derivatives, PNA that was modified with a naphthyl-type tolane could efficiently discriminate a mismatched base pair and be utilized for the detection of resistance to neuraminidase inhibitors of the influenza A/H1N1 virus. Therefore, our molecular tool can be used to discriminate single nucleotide polymorphisms that are related to drug resistance in pathogens. Full article
(This article belongs to the Special Issue Peptide Nucleic Acids: Applications in Biomedical Sciences)
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Article
RNA Secondary Structure-Based Design of Antisense Peptide Nucleic Acids for Modulating Disease-Associated Aberrant Tau Pre-mRNA Alternative Splicing
Molecules 2019, 24(16), 3020; https://doi.org/10.3390/molecules24163020 - 20 Aug 2019
Cited by 10 | Viewed by 2315
Abstract
Alternative splicing of tau pre-mRNA is regulated by a 5′ splice site (5′ss) hairpin present at the exon 10–intron 10 junction. Single mutations within the hairpin sequence alter hairpin structural stability and/or the binding of splicing factors, resulting in disease-causing aberrant splicing of [...] Read more.
Alternative splicing of tau pre-mRNA is regulated by a 5′ splice site (5′ss) hairpin present at the exon 10–intron 10 junction. Single mutations within the hairpin sequence alter hairpin structural stability and/or the binding of splicing factors, resulting in disease-causing aberrant splicing of exon 10. The hairpin structure contains about seven stably formed base pairs and thus may be suitable for targeting through antisense strands. Here, we used antisense peptide nucleic acids (asPNAs) to probe and target the tau pre-mRNA exon 10 5′ss hairpin structure through strand invasion. We characterized by electrophoretic mobility shift assay the binding of the designed asPNAs to model tau splice site hairpins. The relatively short (10–15 mer) asPNAs showed nanomolar binding to wild-type hairpins as well as a disease-causing mutant hairpin C+19G, albeit with reduced binding strength. Thus, the structural stabilizing effect of C+19G mutation could be revealed by asPNA binding. In addition, our cell culture minigene splicing assay data revealed that application of an asPNA targeting the 3′ arm of the hairpin resulted in an increased exon 10 inclusion level for the disease-associated mutant C+19G, probably by exposing the 5′ss as well as inhibiting the binding of protein factors to the intronic spicing silencer. On the contrary, the application of asPNAs targeting the 5′ arm of the hairpin caused an increased exon 10 exclusion for a disease-associated mutant C+14U, mainly by blocking the 5′ss. PNAs could enter cells through conjugation with amino sugar neamine or by cotransfection with minigene plasmids using a commercially available transfection reagent. Full article
(This article belongs to the Special Issue Peptide Nucleic Acids: Applications in Biomedical Sciences)
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Review

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Review
PNA-Based MicroRNA Detection Methodologies
Molecules 2020, 25(6), 1296; https://doi.org/10.3390/molecules25061296 - 12 Mar 2020
Cited by 17 | Viewed by 2523
Abstract
MicroRNAs (miRNAs or miRs) are small noncoding RNAs involved in the fine regulation of post-transcriptional processes in the cell. The physiological levels of these short (20–22-mer) oligonucleotides are important for the homeostasis of the organism, and therefore dysregulation can lead to the onset [...] Read more.
MicroRNAs (miRNAs or miRs) are small noncoding RNAs involved in the fine regulation of post-transcriptional processes in the cell. The physiological levels of these short (20–22-mer) oligonucleotides are important for the homeostasis of the organism, and therefore dysregulation can lead to the onset of cancer and other pathologies. Their importance as biomarkers is constantly growing and, in this context, detection methods based on the hybridization to peptide nucleic acids (PNAs) are gaining their place in the spotlight. After a brief overview of their biogenesis, this review will discuss the significance of targeting miR, providing a wide range of PNA-based approaches to detect them at biologically significant concentrations, based on electrochemical, fluorescence and colorimetric assays. Full article
(This article belongs to the Special Issue Peptide Nucleic Acids: Applications in Biomedical Sciences)
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Review
PNA Clamping in Nucleic Acid Amplification Protocols to Detect Single Nucleotide Mutations Related to Cancer
Molecules 2020, 25(4), 786; https://doi.org/10.3390/molecules25040786 - 12 Feb 2020
Cited by 12 | Viewed by 1565
Abstract
This review describes the application of peptide nucleic acids (PNAs) as clamps that prevent nucleic acid amplification of wild-type DNA so that DNA with mutations may be observed. These methods are useful to detect single-nucleotide polymorphisms (SNPs) in cases where there is a [...] Read more.
This review describes the application of peptide nucleic acids (PNAs) as clamps that prevent nucleic acid amplification of wild-type DNA so that DNA with mutations may be observed. These methods are useful to detect single-nucleotide polymorphisms (SNPs) in cases where there is a small amount of mutated DNA relative to the amount of normal (unmutated/wild-type) DNA. Detecting SNPs arising from mutated DNA can be useful to diagnose various genetic diseases, and is especially important in cancer diagnostics for early detection, proper diagnosis, and monitoring of disease progression. Most examples use PNA clamps to inhibit PCR amplification of wild-type DNA to identify the presence of mutated DNA associated with various types of cancer. Full article
(This article belongs to the Special Issue Peptide Nucleic Acids: Applications in Biomedical Sciences)
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Review
Peptide Nucleic Acids and Gene Editing: Perspectives on Structure and Repair
Molecules 2020, 25(3), 735; https://doi.org/10.3390/molecules25030735 - 08 Feb 2020
Cited by 28 | Viewed by 3287
Abstract
Unusual nucleic acid structures are salient triggers of endogenous repair and can occur in sequence-specific contexts. Peptide nucleic acids (PNAs) rely on these principles to achieve non-enzymatic gene editing. By forming high-affinity heterotriplex structures within the genome, PNAs have been used to correct [...] Read more.
Unusual nucleic acid structures are salient triggers of endogenous repair and can occur in sequence-specific contexts. Peptide nucleic acids (PNAs) rely on these principles to achieve non-enzymatic gene editing. By forming high-affinity heterotriplex structures within the genome, PNAs have been used to correct multiple human disease-relevant mutations with low off-target effects. Advances in molecular design, chemical modification, and delivery have enabled systemic in vivo application of PNAs resulting in detectable editing in preclinical mouse models. In a model of β-thalassemia, treated animals demonstrated clinically relevant protein restoration and disease phenotype amelioration, suggesting a potential for curative therapeutic application of PNAs to monogenic disorders. This review discusses the rationale and advances of PNA technologies and their application to gene editing with an emphasis on structural biochemistry and repair. Full article
(This article belongs to the Special Issue Peptide Nucleic Acids: Applications in Biomedical Sciences)
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Review
Antibacterial Peptide Nucleic Acids—Facts and Perspectives
Molecules 2020, 25(3), 559; https://doi.org/10.3390/molecules25030559 - 28 Jan 2020
Cited by 24 | Viewed by 3296
Abstract
Antibiotic resistance is an escalating, worldwide problem. Due to excessive use of antibiotics, multidrug-resistant bacteria have become a serious threat and a major global healthcare problem of the 21st century. This fact creates an urgent need for new and effective antimicrobials. The common [...] Read more.
Antibiotic resistance is an escalating, worldwide problem. Due to excessive use of antibiotics, multidrug-resistant bacteria have become a serious threat and a major global healthcare problem of the 21st century. This fact creates an urgent need for new and effective antimicrobials. The common strategies for antibiotic discovery are based on either modifying existing antibiotics or screening compound libraries, but these strategies have not been successful in recent decades. An alternative approach could be to use gene-specific oligonucleotides, such as peptide nucleic acid (PNA) oligomers, that can specifically target any single pathogen. This approach broadens the range of potential targets to any gene with a known sequence in any bacterium, and could significantly reduce the time required to discover new antimicrobials or their redesign, if resistance arises. We review the potential of PNA as an antibacterial molecule. First, we describe the physicochemical properties of PNA and modifications of the PNA backbone and nucleobases. Second, we review the carriers used to transport PNA to bacterial cells. Furthermore, we discuss the PNA targets in antibacterial studies focusing on antisense PNA targeting bacterial mRNA and rRNA. Full article
(This article belongs to the Special Issue Peptide Nucleic Acids: Applications in Biomedical Sciences)
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Other

Brief Report
A Peptide Nucleic Acid (PNA) Masking the miR-145-5p Binding Site of the 3′UTR of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mRNA Enhances CFTR Expression in Calu-3 Cells
Molecules 2020, 25(7), 1677; https://doi.org/10.3390/molecules25071677 - 05 Apr 2020
Cited by 8 | Viewed by 1410
Abstract
Peptide nucleic acids (PNAs) have been demonstrated to be very useful tools for gene regulation at different levels and with different mechanisms of action. In the last few years the use of PNAs for targeting microRNAs (anti-miRNA PNAs) has provided impressive advancements. In [...] Read more.
Peptide nucleic acids (PNAs) have been demonstrated to be very useful tools for gene regulation at different levels and with different mechanisms of action. In the last few years the use of PNAs for targeting microRNAs (anti-miRNA PNAs) has provided impressive advancements. In particular, targeting of microRNAs involved in the repression of the expression of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is defective in cystic fibrosis (CF), is a key step in the development of new types of treatment protocols. In addition to the anti-miRNA therapeutic strategy, inhibition of miRNA functions can be reached by masking the miRNA binding sites present within the 3′UTR region of the target mRNAs. The objective of this study was to design a PNA masking the binding site of the microRNA miR-145-5p present within the 3′UTR of the CFTR mRNA and to determine its activity in inhibiting miR-145-5p function, with particular focus on the expression of both CFTR mRNA and CFTR protein in Calu-3 cells. The results obtained support the concept that the PNA masking the miR-145-5p binding site of the CFTR mRNA is able to interfere with miR-145-5p biological functions, leading to both an increase of CFTR mRNA and CFTR protein content. Full article
(This article belongs to the Special Issue Peptide Nucleic Acids: Applications in Biomedical Sciences)
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