RNA interference trigger variants: getting the most out of RNA for RNA interference-based therapeutics

Abstract

The manifestation of RNA interference (RNAi)-based therapeutics lies in safe and successful delivery of small interfering RNAs (siRNAs), the molecular entity that triggers and guides sequence-specific degradation of target mRNAs. Optimizing the chemistry and structure of siRNAs to achieve maximum efficacy is an important parameter in the development of siRNA therapeutics. The RNAi protein machinery can tolerate a variety of non-canonical modifications made to siRNAs, each of which imparts advantageous properties. Here, we review these modifications to siRNAs in pre-clinical and clinical studies.

FIG. 1.

Schematic depicting perfectly complementary argonaute (Ago)2-mediated RNA interference (RNAi) in mammalian cells. RNAi triggers with the canonical siRNA structure do not require Dicer processing, whereas longer RNAi triggers will be processed by Dicer to enter the RNAi pathway. There is some evidence that longer RNAi triggers can be loaded into Ago2/RNA induced silencing complex (RISC) directly, but this model remains to be thoroughly tested. Red strands=passenger strands. Blue strands=guide strands. Figure is not drawn to scale.

FIG. 2.

Schematic of a canonical siRNA and several chemical and structural variations. The chemically modified small interfering RNA (siRNA) is not any specific siRNA reported in the literature, but rather a generic illustration of where some of the indicated chemical modifications can be placed. Red strands=passenger strands. Blue strands=guide strands. Dashed vertical grey line denotes the 5′ end of the guide strand of a canonical siRNA and the predicted 5′ end of the guide strand after Dicer processing for longer RNAi triggers. Figures not drawn to scale.