Expanding the Horizon of the Xeno Nucleic Acid Space: Threose Nucleic Acids with Increased Information Storage,Journal of the American Chemical Society

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Expanding the Horizon of the Xeno Nucleic Acid Space: Threose Nucleic Acids with Increased Information Storage
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2024-03-05 , DOI: 10.1021/jacs.3c14626
Hannah Depmeier ₁ , Stephanie Kath-Schorr ₁

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Xeno nucleic acids (XNAs) constitute a class of synthetic nucleic acid analogues characterized by distinct, non-natural 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 natural-like 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.

中文翻译：

扩大异种核酸空间的视野：具有增加信息存储的苏糖核酸

异种核酸（XNA）构成一类合成的核酸类似物，其特征在于核酸聚合物的三联结构内的独特的、非天然的修饰。虽然大多数所描述的 XNA 仅在核酸支架的一个结构元件中包含修饰，但这项工作探索了 XNA 化学空间，以通过在核苷支架的多个部分中进行修饰来创建更多不同的变体。结合α- l-苏呋喃糖基核酸（TNA）增强的核酸酶抗性和非天然疏水碱基对（UBP） TPT3 ： NaM的近乎天然的复制效率和保真度，合成了具有双重修饰模式的新型修饰核苷三磷酸。我们研究了 XNA 兼容聚合酶对这些核苷酸构件的酶促掺入，并证实了TPT3修饰的 TNA 的成功酶促合成，而NaM修饰的 TNA 的制备提出了更大的挑战。这项研究标志着首次酶法合成具有扩展遗传字母表 (exTNA) 的 TNA，为核酸治疗开辟了充满希望的机会，特别是对于化学多样性增加的抗核酸酶、高亲和力适体的选择和进化。

更新日期：2024-03-05

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