Crystal structure, stability and Ago2 affinity of phosphorodithioate-modified RNAs

Abstract

Small interfering RNAs (siRNAs) with phosphorodithioate modifications (PS2-RNA) possess favourable properties for use as RNAi therapeutics. Beneficial here is the combining of PS2 and 20 -O-methyl modifications (MePS2). SiRNAs with MePS2 moieties in the sense strand show promising efficacies in vitro and in vivo. Crystal structures of PS2- and MePS2- modified RNAs reveal subtle changes in geometry and hydration compared with natural RNA. A model of an MePS2- RNA–PAZ domain complex points to a hydrophobic effect as the source of the higher affinity of MePS2-RNA for Ago2.

RSC Adv., 2014, 4, 64901