000 | 02102 am a22002533u 4500 | ||
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042 | _adc | ||
100 | 1 | 0 |
_aTaylor, Alexander I. _eauthor _91456 |
700 | 1 | 0 |
_aWan, Christopher J.K. _eauthor _91457 |
700 | 1 | 0 |
_aDonde, Maria J. _eauthor _91458 |
700 | 1 | 0 |
_aPeak-Che _eauthor _91459 |
700 | 1 | 0 |
_aHolliger, Philipp _eauthor _91460 |
245 | 0 | 0 | _aA modular XNAzyme cleaves long, structured RNAs under physiological conditions and enables allele-specific gene silencing |
260 | _c2022-11. | ||
500 | _a/pmc/articles/PMC7613789/ | ||
500 | _a/pubmed/36064973 | ||
520 | _aNucleic acid catalysts (ribozymes, DNA- and XNAzymes) cleave target (m)RNAs with high specificity but have shown limited efficacy in clinical application. Here we report on the in vitro evolution and engineering of a highly specific modular RNA endonuclease XNAzyme, FR6_1, composed of 2'-deoxy-2'-fluoro-β-D-arabino nucleic acid (FANA). FR6_1 overcomes activity limitations of previous DNA- and XNAzymes and can be retargeted to cleave highly structured full-length (>5 kb) BRAF and KRAS mRNAs at physiological Mg(2+) concentrations with allelic selectivity for tumour-associated (BRAF V600E and KRAS G12D) mutations. Phosphorothioate-FANA modification enhances FR6_1 biostability and enables rapid KRAS mRNA knockdown in cultured human adenocarcinoma cells with a G12D-allele-specific component provided by in vivo XNAzyme cleavage activity. These results provide a starting point for the development of improved gene silencing agents based on FANA or other XNA chemistries. | ||
540 | _a | ||
540 | _ahttps://www.springernature.com/gp/open-research/policies/accepted-manuscript-termsUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: https://www.springernature.com/gp/open-research/policies/accepted-manuscript-terms | ||
546 | _aen | ||
690 | _aArticle | ||
655 | 7 |
_aText _2local |
|
786 | 0 | _nNat Chem | |
856 | 4 | 1 |
_uhttp://dx.doi.org/10.1038/s41557-022-01021-z _zConnect to this object online. |
999 |
_c809 _d809 |