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Review
. 2023 Oct 23;15(10):2515.
doi: 10.3390/pharmaceutics15102515.

Recent Advancements in Development and Therapeutic Applications of Genome-Targeting Triplex-Forming Oligonucleotides and Peptide Nucleic Acids

Affiliations
Review

Recent Advancements in Development and Therapeutic Applications of Genome-Targeting Triplex-Forming Oligonucleotides and Peptide Nucleic Acids

Yu Mikame et al. Pharmaceutics. .

Abstract

Recent developments in artificial nucleic acid and drug delivery systems present possibilities for the symbiotic engineering of therapeutic oligonucleotides, such as antisense oligonucleotides (ASOs) and small interfering ribonucleic acids (siRNAs). Employing these technologies, triplex-forming oligonucleotides (TFOs) or peptide nucleic acids (PNAs) can be applied to the development of symbiotic genome-targeting tools as well as a new class of oligonucleotide drugs, which offer conceptual advantages over antisense as the antigene target generally comprises two gene copies per cell rather than multiple copies of mRNA that are being continually transcribed. Further, genome editing by TFOs or PNAs induces permanent changes in the pathological genes, thus facilitating the complete cure of diseases. Nuclease-based gene-editing tools, such as zinc fingers, CRISPR-Cas9, and TALENs, are being explored for therapeutic applications, although their potential off-target, cytotoxic, and/or immunogenic effects may hinder their in vivo applications. Therefore, this review is aimed at describing the ongoing progress in TFO and PNA technologies, which can be symbiotic genome-targeting tools that will cause a near-future paradigm shift in drug development.

Keywords: antigene; genome editing; oligonucleotide therapeutic; peptide nucleic acid; triplex-forming oligonucleotide.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structural features of TFO. The parallel and antiparallel triplexes (orange) are formed by Hoogsteen hydrogen-bond interactions (light blue) and reverse Hoogsteen hydrogen-bond interactions (light green), respectively.
Figure 2
Figure 2
(a) Triplex formation perturbs DNA transcription and replication (the green, red, and yellow represent the transcriptional factors). (b) Triplex formation distorts the DNA duplex structure and induces DNA DSBs, which can be exploited for genome editing or (c) induce cell apoptosis. (d) TFO (orange) can provide a sequence selectivity to functional molecules (FG) that interact with ds DNA (blue).
Figure 3
Figure 3
Selected examples of the artificial nucleobases developed for T:A and C:G inversions.
Figure 4
Figure 4
Selected examples of other types of triplex-stabilizing artificial nucleobases.
Figure 5
Figure 5
Structures of the psoralen-conjugated TFOs (Ps–TFOs) and psoralen N-hydroxysuccinimide (NHS) esters. The charts show the crosslinking efficiencies of the corresponding Ps–TFOs prepared using each NHS ester (the charts were quoted from [57]).
Figure 6
Figure 6
Structures of Pt–TFOs.
Figure 7
Figure 7
Structures of AMN–TFO (part of the figure was modified, following [72,73]).
Figure 8
Figure 8
Structural features of PNA and unique mode of PNA actions.
Figure 9
Figure 9
Chemical modifications of the PNA backbone. The position of the carbon is mentioned using α, β, γ (red).
Figure 10
Figure 10
Nucleobase modifications of PNA.

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