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1. Stimuli-responsive assembly of bilingual peptide nucleic acids

   https://doi.org/10.1039/D2CB00020B  

   Argueta-Gonzalez, Hector S.; Swenson, Colin S.; Song, George; Heemstra, Jennifer M. (June 2022, RSC Chemical Biology)

   Peptide nucleic acids (PNAs) are high-affinity synthetic nucleic acid analogs capable of hybridization with native nucleic acids. PNAs synthesized having amino acid sidechains installed at the γ-position along the backbone provide a template for a single biopolymer to simultaneously encode nucleic acid and amino acid sequences. Previously, we reported the development of “bilingual” PNAs through the synthesis of an amphiphilic sequence featuring separate blocks of hydrophobic and hydrophilic amino acid functional groups. These PNAs combined the sequence-specific binding activity of nucleic acids with the structural organization properties of peptides. Like other amphiphilic compounds, these γ-PNAs were observed to assemble spontaneously into micelle-like nanostructures in aqueous solutions and disassembly was induced through hybridization to a complementary sequence. Here, we explore whether assembly of these bilingual PNAs is possible by harnessing the nucleic acid code. Specifically, we designed an amphiphile-masking duplex system in which spontaneous amphiphile assembly is prevented through hybridization to a nucleic acid masking sequence. We show that the amphiphile is displaced upon introduction of a releasing sequence complementary to the masking sequence through toehold mediated displacement. Upon release, we observe that the amphiphile proceeds to assemble in a fashion consistent with our previously reported structures. Our approach represents a novel method for controlled stimuli-responsive assembly of PNA-based nanostructures. 

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2. 5-Triazolyl uracil improves nucleobase stacking, pyrimidine recognition, biological activity, and specificity of RNA-binding triplex-forming peptide nucleic acids

   https://doi.org/10.1093/nar/gkag249  

   Saei, Sara F; Endoh, Tamaki; Baskevics, Vladislavs; Kumpina, Ilze; Katkevics, Martins; Sugimoto, Naoki; Rozners, Eriks (March 2026, Nucleic Acids Research)

   Cellular RNA folds into complex helical structures that are attractive targets for controlling biological activity and treating diseases using RNA-binding ligands. Peptide nucleic acid (PNA) is a neutral DNA analog uniquely suited for triple-helical recognition of RNA. However, the applications of triplex-forming PNAs have been limited by sequence restrictions, as stable base triples are formed only with purines. Hoogsteen recognition of pyrimidines has been a long-standing challenge. The present study explores a new approach to improve pyrimidine recognition by enhancing nucleobase stacking in the PNA strand. Placing 5-triazolyl uracil adjacent to the modified nucleobases designed for pyrimidine recognition increased the binding affinity while maintaining sequence specificity. Molecular dynamics simulations confirmed the beneficial effect of synergistic stacking interactions between the triazole and neighboring nucleobases. The increased binding affinity improved the biological activity of triplex-forming PNAs targeting microRNA precursors in a cell-based dual fluorescent protein assay. RNA-seq analysis showed that a PNA recognizing a mixed sequence of three nucleobases (G, A, and U) had higher specificity than a similar PNA featuring a uniform purine recognition tract. These results demonstrate a novel strategy for addressing the issue of pyrimidine recognition, a critical bottleneck in the triple helical targeting of nucleic acids. 

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3. Delocalization-Assisted Transport through Nucleic Acids in Molecular Junctions

   https://doi.org//10.1021/acs.biochem.1c00072  

   Jesús Valdiviezo, Caleb Clever (April 2021, Biochemistry)

   null (Ed.)

   The flow of charge through molecules is central to the function of supramolecular machines, and charge transport in nucleic acids is implicated in molecular signaling and DNA repair. We examine the transport of electrons through nucleic acids to understand the interplay of resonant and nonresonant charge carrier transport mechanisms. This study reports STM break junction measurements of peptide nucleic acids (PNAs) with a Gblock structure and contrasts the findings with previous results for DNA duplexes. The conductance of G-block PNA duplexes is much higher than that of the corresponding DNA duplexes of the same sequence; however, they do not display the strong even−odd dependence conductance oscillations found in G-block DNA. Theoretical analysis finds that the conductance oscillation magnitude in PNA is suppressed because of the increased level of electronic coupling interaction between G-blocks in PNA and the stronger PNA−electrode interaction compared to that in DNA duplexes. The strong interactions in the G-block PNA duplexes produce molecular conductances as high as 3% G0, where G0 is the quantum of conductance, for 5 nm duplexes. 

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4. 2-Aminopyridine nucleobases enable DNA invasion by peptide nucleic acid clamps under physiological conditions

   https://doi.org/10.1039/D4CC06748G  

   Tessier, Brandon R; Rozners, Eriks (March 2025, Chemical Communications)

   Peptide nucleic acid (PNA) clamps modified with 2-aminopyridine (M) nucleobase invaded double-stranded DNA under physiological salt conditions. In contrast, PNAs carrying common nucleobases could not fully invade DNA under these conditions. M-modified PNAs may overcome the problematic requirement for low salt concentration, a long-standing DNA invasion problem. 

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5. A universal discoidal nanoplatform for the intracellular delivery of PNAs

   https://doi.org/10.1039/c9nr03667a  

   Tahmasbi Rad, Armin; Malik, Shipra; Yang, Lin; Oberoi-Khanuja, Tripat Kaur; Nieh, Mu-Ping; Bahal, Raman (July 2019, Nanoscale)

   null (Ed.)

   Peptide nucleic acids (PNAs) have gained considerable attention due to their remarkable potential in gene editing and targeting-based strategies. However, cellular delivery of PNAs remains a challenge in developing their broader therapeutic applications. Here, we investigated a novel complex made of lipid bicelles and PNA-based carriers for the efficient delivery of PNAs. For proof of concept, PNAs targeting microRNA (miR) 210 and 155 were tested. Comprehensive evaluation of positive as well as negative charge-containing bicelles with PNA : lipid ratios of 1 : 100, 1 : 1000, and 1 : 2500 was performed. The negatively charged bicelles with a PNA : lipid molar ratio of 1 : 2500 yielded a discoidal shape with a uniform diameter of ∼30 nm and a bilayer thickness of 5 nm, while the positively charged bicellar system contained irregular vesicles after the incorporation of PNA. Small-angle X-ray scattering (SAXS) analysis was performed to provide insight into how the hydrophobic PNAs interact with bicelles. Further, flow cytometry followed by confocal microscopy analyses substantiate the superior transfection efficiency of bicelles containing dye-conjugated antimiR PNAs. Functional analysis also confirmed miR inhibition by PNA oligomers delivered by bicelles. The nanodiscoidal complex opens a new pathway to deliver PNAs, which, on their own, are a great challenge to be endocytosed into cells. 

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