Bifacial Peptide Nucleic Acids (bPNAs) utilize synthetic triazine bases to form triplex hybrid stems with oligo T/U domains that are biomimetic of native triple stranded structures formed from UAU base-triples. Indeed, bPNAs can displace oligo-A strands from U-rich internal loops (URILs) to form a synthetic triplex hybrid. We report herein low molecular weight (&lt;1 kD) bPNAs capable of selective intracellular labeling of RNAs containing U-rich internal loops (URILs). Pre-structured URILs, which are relatively rare, were found to be particularly selective for bPNA binding even among other native U-rich transcripts. This enables selective targeting, pulldown and triggered degradation of native URILs, as found in lncRNAs NEAT1 and MALAT1 (NEAT2). Furthermore, engineered URILs enable fluorogenic bPNA labeling of RNAs of interest and associated RNA-protein complexes. We anticipate that this and related bPNA targeting strategies will be useful for interrogation of intracellular RNA interactions.

Intracellular targeting of RNA and RNA-protein interactions via biomimetic triplex hybridization with bPNAs

ACS Spring 2022

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