Recent Progress in Chemically Modified siRNAs

Abstract

RNA interference technology has become a powerful laboratory tool to study gene function. Small interfering RNAs (siRNAs) have provided unprecedented opportunities for the development of new therapeutics in human diseases. Unfortunately, siRNA duplexes are not optimal drug-like molecules. The problems for their effective application are fundamentally delivery, stability and off-target effects. Chemical modification provides solutions to many of the challenges facing siRNA therapeutics. In this review, we recapitulate and discuss the development of the latest described chemical modifications of siRNAs, with a special focus on novel chemical modifications of siRNA structure, architecture and siRNA conjugates.

Structure - Functions Relations in Small Interfering RNAs

“…Conjugation of siRNAs with the lipophilic molecules (cholesterol, derivatives of the oleic, lithocholic and lauric acids), peptides, antibodies, aptamers and other compounds is an effective tool to overcome this problem [132,133]. The cholesterol was suggested as the first candidate for conjugation, since the natural mechanisms of cholesterol transport exist in mammalian organisms.…”

Research progress on siRNA delivery with nonviral carriers

“…23 Phosphorothioate (P = S) modifications can be placed in the RNA duplex easily at any desired position and will enhance the stability of siRNA in nuclease environments. Overhoff and Sczakiel stated that phosphorothioate (PTO)-derived oligonucleotides stimulate the physical cellular uptake of siRNA in human cells.…”

Selection and Optimization of Asymmetric siRNA Targeting the Human c-MET Gene

“…Recently, a phase 3 clinical trial of a first-in-class siRNA drug targeting vascular endothelial growth factor (VEGF) was terminated because the siRNA stimulated the sequence non-specific toll-like receptor 3 (TLR3) (Kleinman et al, 2008). Many groups have tested chemical or structural modifications to overcome the current hurdles of siRNA technology (Chu and Rana, 2008;Gaglione and Messere, 2010;Grimm, 2009;Sano et al, 2008;Sun et al, 2008). asiRNA, developed by our group, is one structural variation with reduced side effects (Chang et al, 2009).…”