Tailoring Peptide Nucleic Acids for Advanced Antisense Therapeutics

Abstract

Peptide nucleic acids (PNAs) are synthetic analogs that replicate the function of natural nucleic acids, featuring a backbone consisting of N-(2-aminoethyl)glycine units instead of the typical sugar-phosphate structure. This unique design allows PNAs to exhibit strong resistance to degradation by enzymes like proteases and nucleases and to form highly stable and specific complexes with RNA and DNA.[1] However, their limited solubility in water has posed challenges for their use in biological systems, raising concerns about their potential toxicity. To address them, a modified version known as γ miniPEG-PNA has been developed by integrating diethylene glycol groups into the PNA backbone to improve solubility.[2] To explore the properties of these compounds, both conventional PNAs and γ miniPEGPNAs are synthesized using solid-phase peptide synthesis, purified and characterized via mass spectrometry. The binding affinities of various duplexes, including RNA/RNA, RNA/PNA, and RNA/γ-miniPEG-PNA, are studied through surface plasmon resonance spectroscopy. These investigations aim to overcome present limitations and advance the understanding and practical application potential of PNAs.