Applications of (<scp>l</scp>)-<i>Acyclic</i> Threoninol Nucleic Acids

ConspectusThe emerging class of (l)-<i>acyclic</i> threoninol nucleic acids ((l)-<i>a</i>TNAs) represents a novel type of xeno nucleic acids (XNAs), characterized by an acyclic nonribose backbone derived from the amino acid threonine. In this Account, the distinctive structural characteristics and broad spectrum of applications of (l)-<i>a</i>TNA are described. Compared to DNA and RNA, (l)-<i>a</i>TNA exhibits enhanced flexibility and conformational diversity. This flexibility, surprisingly, does not compromise but rather enhances the molecule's stability in homoduplex formation, and it also forms stable heteroduplexes with both DNA and RNA. This unique structural configuration not only contributes to a remarkable resistance to nuclease degradation but also significantly extends its <i>in vivo</i> stability compared to natural nucleic acids, making (l)-<i>a</i>TNA a highly durable biomolecule for various applications.One of the standout properties of (l)-<i>a</i>TNA is its ability to adopt a range of highly stable secondary structures, such as triplexes, G-quadruplexes, and i-motifs. This ability is maintained even under conditions such as low ionic strength, underscoring its potential utility in bioanalytical applications and therapy. The molecule's versatility is further exemplified by its use in biotechnological applications, including toehold-mediated strand displacement reactions, which are important for constructing dynamic molecular systems that can respond to environmental cues with high specificity and stability. Moreover, (l)-<i>a</i>TNA's capability to regulate gene expression through the formation of stable triplex structures presents promising potential for gene therapy, offering a method to control gene activity with precision. In the realm of drug delivery, the robustness of (l)-<i>a</i>TNA constructs, particularly in forming four-way junctions, underscores its efficacy under physiological conditions, highlighting its potential in creating drug delivery systems that exhibit minimal immune responses and no cytotoxicity. Additionally, the application of (l)-<i>a</i>TNA in nonenzymatic primer extension experiments provides crucial insights into the mechanisms of prebiotic chemistry and supports the pre-RNA world hypothesis. Recently, it was also demonstrated that the high stability of (l)-<i>a</i>TNA homoduplexes can be used in nucleic acid nanotechnology to assemble into ultrasmall 3D architectures with the potential for targeting and improved tissue penetration. The structural and chemical properties of (l)-<i>a</i>TNA, especially its enhanced thermal stability and resistance to enzymatic degradation, make it a promising tool in the fields of molecular biology, nanotechnology, and therapeutic development.