Functional nucleic acids with synthetic sugar or nucleobase moieties

Zhang, Ze; Chen, Siqi; Li, Zhe; Yu, Henry

doi:10.1016/j.aac.2023.08.001

“…16 This work emphasizes the profound significance of the development of novel XNAs with a dual modification pattern in both the sugar backbone and the nucleobase. 32 However, the approach itself is still limited to the recognition of the four canonical nucleobases by Watson−Crick base pairing. Selective introduction of individual modifications is not possible.…”

Section: ■ Introductionmentioning

confidence: 99%

Expanding the Horizon of the Xeno Nucleic Acid Space: Threose Nucleic Acids with Increased Information Storage

Depmeier,

Kath-Schorr

2024

J. Am. Chem. Soc.

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Xeno nucleic acids (XNAs) constitute a class of synthetic nucleic acid analogues characterized by distinct, nonnatural modifications within the tripartite structure of the nucleic acid polymers. While most of the described XNAs contain a modification in only one structural element of the nucleic acid scaffold, this work explores the XNA chemical space to create more divergent variants with modifications in multiple parts of the nucleosidic scaffold. Combining the enhanced nuclease resistance of α-L-threofuranosyl nucleic acid (TNA) and the almost naturallike replication efficiency and fidelity of the unnatural hydrophobic base pair (UBP) TPT3:NaM, novel modified nucleoside triphosphates with a dual modification pattern were synthesized. We investigated the enzymatic incorporation of these nucleotide building blocks by XNA-compatible polymerases and confirmed the successful enzymatic synthesis of TPT3-modified TNA, while the preparation of NaM-modified TNA presented greater challenges. This study marks the first enzymatic synthesis of TNA with an expanded genetic alphabet (exTNA), opening promising opportunities in nucleic acid therapeutics, particularly for the selection and evolution of nuclease-resistant, high-affinity aptamers with increased chemical diversity.

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Enzymatic Synthesis of TNA Protects DNA Nanostructures

Qin,

Wang,

Wang

et al. 2024

Angewandte Chemie

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Xeno‐nucleic acids (XNAs) are synthetic genetic polymers with improved biological stabilities and offer powerful molecular tools such as aptamers and catalysts. However, XNA application has been hindered by a very limited repertoire of tool enzymes, particularly those that enable de novo XNA synthesis. Here we report that terminal deoxynucleotide transferase (TdT) catalyzes untemplated threose nucleic acid (TNA) synthesis at the 3’ terminus of DNA oligonucleotide, resulting in DNA‐TNA chimera resistant to exonuclease digestion. Moreover, TdT‐catalyzed TNA extension supports one‐pot batch preparation of biostable chimeric oligonucleotides, which can be used directly as staples during self‐assembly of DNA origami nanostructures (DONs). Such TNA‐protected DONs show enhanced biological stability in the presence of exonuclease I, DNase I and fetal bovine serum. This work not only expands the available enzyme toolbox for XNA synthesis and manipulation, but also provides a promising approach to fabricate DONs with improved stability under the physiological condition.

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Enzymatic Synthesis of TNA Protects DNA Nanostructures

Qin,

Wang,

Wang

et al. 2024

Angew Chem Int Ed

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5

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Xeno‐nucleic acids (XNAs) are synthetic genetic polymers with improved biological stabilities and offer powerful molecular tools such as aptamers and catalysts. However, XNA application has been hindered by a very limited repertoire of tool enzymes, particularly those that enable de novo XNA synthesis. Here we report that terminal deoxynucleotide transferase (TdT) catalyzes untemplated threose nucleic acid (TNA) synthesis at the 3’ terminus of DNA oligonucleotide, resulting in DNA‐TNA chimera resistant to exonuclease digestion. Moreover, TdT‐catalyzed TNA extension supports one‐pot batch preparation of biostable chimeric oligonucleotides, which can be used directly as staples during self‐assembly of DNA origami nanostructures (DONs). Such TNA‐protected DONs show enhanced biological stability in the presence of exonuclease I, DNase I and fetal bovine serum. This work not only expands the available enzyme toolbox for XNA synthesis and manipulation, but also provides a promising approach to fabricate DONs with improved stability under the physiological condition.

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Functional nucleic acids with synthetic sugar or nucleobase moieties

Cited by 5 publications

References 88 publications

Expanding the Horizon of the Xeno Nucleic Acid Space: Threose Nucleic Acids with Increased Information Storage

Expanding the Horizon of the Xeno Nucleic Acid Space: Threose Nucleic Acids with Increased Information Storage

Enzymatic Synthesis of TNA Protects DNA Nanostructures

Enzymatic Synthesis of TNA Protects DNA Nanostructures

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