Peptide nucleic acid-based targeting of microRNAs: possible therapeutic applications for glioblastoma

Abstract

A large and incremental number of non-coding RNAs, including microRNAs (miRNAs) have been recently demonstrated to play a very important role in human pathologies, including cancer. Therefore, microRNAs have been proposed as therapeutic targets and molecules exhibiting anti-miRNA activity or mimicking functional miRNAs have been developed. Among biomolecules proposed in anti-miRNA therapy, peptide nucleic acids (PNAs) are appealing, in consideration of their stability and efficacy in recognizing RNA targets. PNAs against tumor associated miRNAs have proven to be efficient in inducing anti-tumor effects both in vitro and in vivo. For instance, PNAs targeting miR-155-5p are able to induce apoptosis in glioma cell lines and to enhance the sensitivity to temozolomide (TMZ) in TMZ resistant glioma cells. In vivo, PNAs anti-miR-21 were found to exhibit anti-tumor effects associated with improved survival when administered to animals with intracranial gliomas.

Nanoligomers Targeting Human miRNA for the Treatment of Severe COVID-19 Are Safe and Nontoxic in Mice

“…PNA can thus be utilized as inhibitory therapeutics that tightly attach to their target, in comparison to DNA-based technologies optimized for the dynamic kinetics of DNA binding. − PNAs can be synthesized in specific base pair sequences complementary to desired targets in an RNA or DNA genome. Furthermore, PNAs have previously been applied to specifically bind miRNAs and modulate immune response, fight tumors, detect biomarkers, or serve as biosupramolecular tags . However, until recently, antisense technologies have faced a variety of challenges in clinical translation despite their versatility in targeting nucleic acid sequences.…”

Therapeutic and diagnostic applications of antisense peptide nucleic acids

“…While comprehensive analyses have been conducted to reveal the expression profile of these ncRNAs in certain cancer types, tumor tissues are highly heterogeneous with respect to their molecular and genetic features, supporting the concept that variability of these targets may exist among patients. 60 Thus, the therapeutic intervention of using PNA targeting ncRNA in patients may require an analysis of tumor tissues prior to administration to confirm their expression pattern, which can be done via liquid or surgery-based biopsies. 60 To avoid the invasive nature of surgery-based biopsies, only ncRNAs with fully established roles in tumorigenesis should be considered as PNA targets.…”

“… 60 Thus, the therapeutic intervention of using PNA targeting ncRNA in patients may require an analysis of tumor tissues prior to administration to confirm their expression pattern, which can be done via liquid or surgery-based biopsies. 60 To avoid the invasive nature of surgery-based biopsies, only ncRNAs with fully established roles in tumorigenesis should be considered as PNA targets.…”

Molecular Assembly of Triplex of Duplexes from Homothyminyl-Homocytosinyl Cγ(S/R)-Bimodal Peptide Nucleic Acids with dA8/dG6 and the Cell Permeability of Bimodal Peptide Nucleic Acids

“…Peptide nucleic acids (PNAs) are acyclic DNA analogues with an achiral backbone composed of repeating units of aminoethyl glycine ( aeg ) (Figure a) in which the nucleobases (A/T/C/G) are linked to each aeg unit via a tertiary amide group. , The interbase distance in PNA matches that in DNA/RNA (Figure b), allowing the PNA strand to form canonical base pairing with complementary DNA/RNA strands, leading to stable duplexes in a sequence-specific manner. , The stability of PNA:DNA/RNA duplexes is higher than DNA:DNA/RNA duplexes and the sequence fidelity imparts a unique property to PNA strands, which can invade DNA duplexes . The high avidity of PNA for complementary DNA/RNA has been employed in various applications for DNA/RNA diagnostics and antisense therapeutics . The simplicity of the PNA structure, ease of synthesis, and its remarkable properties broaden its scope for new applications through backbone modification and conjugation with ligands that recognize cells for use as putative gene regulatory agents. , The chemical substitutions at Cα and Cγ on the aeg -PNA backbone do not significantly impede its hybridization with complementary DNA/RNA. , The introduction of cationic alkylamino, guanidino, and polyethylene glycol substituents at Cα or Cγ of aeg -PNA improved its binding to DNA and cell penetration. , One class of modifications that constrains the aeg backbone is by intraresidue cyclization to five-membered cyclopentyl, proline/pyrrolidine rings or six-membered cyclohexyl moieties, which introduces conformational pre-organization, leading to preferential hybridization with DNA or RNA. , …”