Base-pairing properties enable RNA to fold into intricate three-dimensional structures that result in its diverse cellular functions. Given the importance of RNA in human health and disease, targeting RNAs based on their unique structures is a potentially transformative diagnostic and therapeutic strategy. Furthermore, structure-specific reagents open the door to develop novel tools to study RNA function. Here, I will describe our recent efforts aimed at targeting structured RNAs using L-(deoxy)ribose-based nucleic acids (L-DNA and L-RNA), which are mirror images (enantiomers) of native D-nucleotides. Because oligonucleotides of opposite stereochemistry (D versus L) are incapable of forming contiguous Watson–Crick base pairs with each other, we are able to evolve L-oligonucleotide-based aptamers (L-aptamers) that adaptively bind structured D-RNA targets through highly specific tertiary interactions rather than simple hybridization. Recently, we combined the mirror-image approach with modified nucleotides in order to generate, for the first time, L-aptamers with expanded chemical functionality. We show that introducing cationic functional groups onto the L-oligonucleotide scaffold enables isolation of modified L-aptamers with superior RNA-binding properties, which are capable of modulating RNA function. In addition to L-aptamers, we have developed a “cross-chiral” ribonuclease ribozyme that is capable of cleaving structured RNAs of the opposite chirality. Details regarding isolation and characterization of these functional L-oligonucleotides, as well as their potential biomedical applications, will be discussed.

Mirror image aptamers and ribozymes: Targeting RNA through heterochiral nucleic acid interactions

255th National Meeting (2018)

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