Abstract
Chemically synthesized short interfering RNAs (siRNAs) mediate gene silencing in sequence-specific manner by utilizing the endogenous mechanism of RNA interference (RNAi). Synthetic siRNAs are often modified for improving their potency, stability, and for reducing undesirable “off-target” effects. Modification of the internucleotide bond in RNA chain, involving substitution of a single non-bridging phosphate oxygen with sulfur leads to the phosphorothioate (PS) derivatives of RNA. Substitution of both non-bridging phosphate oxygen atoms with sulfur gives rise to a phosphorodithioate (PS2) internucleotide linkage. We used a novel type of PS2-siRNA duplexes and tested their silencing activity, stability, and cellular up-take in comparison to PS- or unmodified duplexes. PS2-siRNAs show the A-type structure, characteristic for double-stranded RNA. Incorporation of PS2 substitutions into siRNA duplexes increases their serum stability. Gene silencing effect is strand- and position-dependent, with certain molecules showing significantly higher activity than PS or unmodified siRNAs. PS2 modifications are promising candidates in RNAi research and in therapeutic applications.
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