Xeno nucleic acids (XNA) represent a group of synthetic nucleic acid analogs bearing distinct non-natural modifications in the tripartite structure of nucleic acid polymers. Most currently described XNAs comprise only a modification in a single location of the nucleic acid scaffold. Therefore, exploration of the XNA chemical space for novel, more divergent variants with regard to modifications in more than one part of the nucleic acid scaffold is of major interest. By combining modifications in the alternating sugar-phosphate backbone with expansion of the genetic alphabet by introducing non-canonical nucleobases the XNA chemical space could be further extended.<br/>The increased nuclease resistance of α-L-threofuranosyl nucleic acids (TNA) and the nearly natural-like replication efficiency and fidelity of currently available unnatural base pairs represent promising characteristics for the enzymatic generation of a new XNA with a dual modification pattern in the nucleosidic scaffold. In this context, an unprecedented modified nucleoside triphosphate bearing a dual modification pattern based on an α-L-threofuranosyl sugar backbone and a non-canonical nucleobase was developed. This highly modified nucleotide analog was shown to be compatible with enzymatic XNA oligonucleotide synthesis and represents a first step towards TNA synthesis with an expanded genetic alphabet via an enzymatic approach.

Towards the synthesis of L-α-threofuranosyl nucleoside triphosphates and oligonucleotides with an expanded genetic alphabet

ACS Spring 2022

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