An l‐RNA Aptamer with Expanded Chemical Functionality that Inhibits MicroRNA Biogenesis

To facilitate isolation of l ‐aptamers with novel RNA‐binding properties, we employed a cationic nucleotide, 5‐aminoallyluridine, during the mirror image in vitro selection process. Through this effort, we identified a modified l ‐RNA aptamer (Ml RA) capable of binding oncogenic precursor microRNA 19a (pre‐miR‐19a) with exceptional affinity, and we showed that cationic modification is absolutely critical for binding. Furthermore, formation of the Ml RA–pre‐miR‐19a complex inhibited Dicer‐mediated cleavage of the pre‐miR, thus blocking formation of the mature functional microRNA. The Ml RA reported here not only represents the first l ‐aptamer to be evolved by using modified nucleotides but also the first modified aptamer (of any type) to be selected against a structured RNA target. Our results demonstrate that functionalized l ‐aptamers, which are intrinsically nuclease‐resistant, provide an attractive approach for developing robust RNA‐binding reagents.