Available on-demand - *S.SM01.04.01
Re-engineering RNA Molecules into Therapeutic Agents—The Expanding Universe of Nucleic Acid Modifications
First-generation nucleic acid analogs such as 2¢-deoxy-2′-fluoro-RNA (2′-F RNA), 2′-O-methyl RNA (2′-OMe RNA), and the phosphorothioates (PS-DNA/RNA) have remained staples of oligonucleotide modification strategies in the discovery and optimization of potential RNAi therapeutics.1,2 The first FDA-approved siRNA drug, patisiran (Onpattro) contains eleven 2′-OMe ribonucleotides in the sense and antisense strands formulated in a lipid nanoparticle (LNP) delivery system.3 Despite their overall appeal in terms of enhanced nuclease resistance, increased pairing stability (2′-F/OMe RNAs) and safety, newer analogs are needed to further improve the therapeutic potential of unformulated siRNAs like GalNAc conjugates. The search for oligonucleotides with therapeutic efficacy has given rise to an expanding universe of analogs, including the second-generation 2'-O-(2-methoxyethyl)-RNA (MOE-RNA)4 and the third-generation bicyclic nucleic acids (BNAs or LNAs).5 The key enzyme in RNA interference (RNAi) is Argonaute 2 (Ago2), a dynamic multi-domain enzyme that binds multiple regions of the guide (antisense) and passenger (sense) siRNAs. Considering the complexity of protein-RNA interactions in RNA interference, it is imperative to expand the process of discovery and optimization of modified siRNAs to new analogs.6 We have explored the potential benefits for efficacy of incorporating into siRNAs sugar modifications like N-methylacetamide (NMA), 5′-E-vinylphosphonate (5′-E-VP) and, more recently, xeno-nucleic acid (XNA)7 residues such as glycol nucleic acid (GNA),8 altritol nucleic acid (ANA),9 and threofuranosyl nucleic acid (TNA).10 The talk will summarize siRNA modification strategies with an emphasis on regiospecific interactions between oligonucleotide and Ago2 and how structural insights based on crystallographic data for modified RNAs alone and in complex with Ago2 from molecular modeling studies can guide the choice of chemical modification at a given position of siRNA for optimizing its therapeutic efficacy.
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