Unlocking the potential of chemically modified peptide nucleic acids for RNA-based therapeutics

Abstract

RNA therapeutics have emerged as next-generation therapy for the treatment of many diseases. Unlike small molecules, RNA targeted drugs are not limited by the availability of binding pockets on the protein, but rather utilize Watson crick (WC) base pairing rules to recognize the target RNA and modulate gene expression. Antisense oligonucleotides (ASOs) present a powerful therapeutic approach to treat disorders triggered by genetic alterations. ASOs recognize the cognate site on the target RNA to alter gene expression. Nine single-stranded ASOs have been approved for clinical use and several candidates are in late-stage clinical trials for both rare and common diseases. Several chemical modifications including phosphorothioates, locked nucleic acid, phosphorodiamidate, morpholino, and peptide nucleic acids (PNAs) have been investigated for efficient RNA targeting. PNAs are synthetic DNA mimics where the deoxyribose phosphate backbone is replaced by N-(2-aminoethyl) glycine units. The neutral pseudopeptide backbone of PNAs contributes to enhanced binding affinity and high biological stability. PNAs hybridize with the complementary site in the target RNA and act by a steric hindrance-based mechanism. In the last three decades various PNA designs, chemical modifications, and delivery strategies have been explored to demonstrate their potential as an effective and safe RNA-targeting platform. This review covers the advances in PNA-mediated targeting of coding and non-coding RNAs for a myriad of therapeutic applications.

In vivo interference of pea aphid endosymbiont Buchnera groEL gene by synthetic peptide nucleic acids

“…A critical aspect of the PNA design involves ensuring the uniqueness of the target site. However, owing to the short length of PNAs, full or partial complementary matches with genome regions other than the target gene occur frequently 26 . Our comprehensive genome-wide search revealed that the 10-bp anti- groEL PNA exhibited no sequence matching with any Buchnera genes, except the target groEL , at their translational start codons or Shine-Dalgarno regions.…”

Synthetic Peptide Nucleic Acids in Action:In VivoInterference of thegroELGene from Pea Aphid EndosymbiontBuchnera aphidicola

“…A critical aspect of the PNA design involves ensuring the uniqueness of the target site. However, owing to the short length of PNAs, full or partial complementary matches with genome regions other than the target gene occur frequently[24]. Our comprehensive genome-wide search revealed that the 10-bp anti- groEL PNA exhibited no sequence matching with any Buchnera genes, except the target groEL , at their translational start codons or Shine-Dalgarno regions.…”

RNA‐based medicine: from molecular mechanisms to therapy

“…This chemical structure also confers resistance toward nucleases and proteases. Like PMOs, PNAs are uncharged, leading to strong binding to complementary sequences, but they face a cellular delivery barrier (Pradeep et al , 2023 ). Other chemical modifications that increase the affinity of oligonucleotides for their targets and thereby improve potency and selectivity center on 2′ ribose modifications, such as 2′‐ O ‐methyl (2′‐ O ‐Me), 2′‐ O ‐methoxyethyl (2′ MOE), and 2′‐fluoro (2′‐F; Kulkarni et al , 2021 ).…”