Synthetic nucleic acid analogues are known as xeno nucleic acids (XNAs), which is appropriate because “xeno” means “alien” or “strange.” To date, most XNAs have been just a little strange, containing a modification in only one of the structural elements of the nucleic acid scaffold. But a new XNA has been developed in which multiple parts of the nucleosidic scaffold have been altered.

The new XNA is a threofuranosyl nucleic acid (TNA) that was developed by scientists at the University of Cologne. The scientists, doctoral student Hannah Depmeier and professor of chemistry Stephanie Kath-Schorr, PhD, also developed a new, additional base pair.

Details appeared in the Journal of the American Chemical Society in an article titled, “Expanding the Horizon of the Xeno Nucleic Acid Space: Threose Nucleic Acids with Increased Information Storage.”

“[We combined] 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 … [to synthesize] novel modified nucleoside triphosphates with a dual modification pattern,” the scientists wrote. “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 work could lead to fully artificial XNAs that would have enhanced chemical functionalities. For example, XNAs could be built that would be impervious to natural enzymes. “Our threofuranosyl nucleic acid,” Kath-Schorr said, “is more stable than the naturally occurring nucleic acids DNA and RNA, which brings many advantages for future therapeutic use.”

For the study, the five-carbon sugar deoxyribose, which forms the backbone in DNA, was replaced by a four-carbon sugar. In addition, the number of nucleobases was increased from four to six.

The swapped-out sugar is what allows the TNA to elude the cell’s own degradation enzymes. Degradation has been a problem with nucleic acid–based therapeutics, as synthetically produced RNA that is introduced into a cell is rapidly degraded and loses its effect. The introduction of TNAs into cells that remain undetected could now maintain the effect for longer.

“The built-in unnatural base pair enables alternative binding options to target molecules in the cell,” Depmeier added. Kath-Schorr is certain that such a function could be particularly useful in the development of new aptamers, short DNA or RNA sequences, which can be used for the targeted control of cellular mechanisms. TNAs could also be used for the targeted transport of drugs to specific organs in the body (targeted drug delivery) as well as in diagnostics; they could also be useful for the recognition of viral proteins or biomarkers.

In their paper, the scientists stated that their exploration of the XNA chemical space allowed them to create more divergent variants with modifications in multiple parts of the nucleosidic scaffold. “This study,” they concluded, “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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