Acyclic (S)-glycol nucleic acid (S-GNA) modification of siRNAs improves the safety of RNAi therapeutics while maintaining potency

Structure, conformations, base-pairing, and Ago2 binding of (S)-GNA. (A) RNA-U and (S)-GNA-T nucleotides. (B) GNA nucleotides adopt both gauche and anticonformations when incorporated into RNA. (C) Example of an (S)-GNA-T:RNA-A base pair showing a rotated nucleobase conformation for the GNA nucleotide (arrow). (D) An (S)-GNA-T residue can seamlessly and with optimal geometry replace an RNA nucleotide at position 7 of the antisense strand RNA bound to human Ago2. The RNA strand assumes a kink at that site that is associated with Ile-365 of Ago2 and results in unstacking of bases of nucleotides 6 and 7.