Issue 28, 2023

Development of 8–17 XNAzymes that are functional in cells


DNA enzymes (DNAzymes), which cleave target RNA with high specificity, have been widely investigated as potential oligonucleotide-based therapeutics. Recently, xeno-nucleic acid (XNA)-modified DNAzymes (XNAzymes), exhibiting cleavage activity in cultured cells, have been developed. However, a versatile approach to modify XNAzymes that function in cells has not yet been established. Here, we report an X-ray crystal structure-based approach to modify 8–17 DNAzymes; this approach enables us to effectively locate suitable XNAs to modify. Our approach, combined with a modification strategy used in designing antisense oligonucleotides, rationally designed 8–17 XNAzyme (“X8–17”) that achieved high potency in terms of RNA cleavage and biostability against nucleases. X8–17, modified with 2′-O-methyl RNA, locked nucleic acid and phosphorothioate, successfully induced endogenous MALAT-1 and SRB1 RNA knockdown in cells. This approach may help in developing XNAzyme-based novel therapeutic agents.

Graphical abstract: Development of 8–17 XNAzymes that are functional in cells

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Article information

Article type
Edge Article
13 Apr 2023
20 Jun 2023
First published
28 Jun 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2023,14, 7620-7629

Development of 8–17 XNAzymes that are functional in cells

K. Chiba, T. Yamaguchi and S. Obika, Chem. Sci., 2023, 14, 7620 DOI: 10.1039/D3SC01928D

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