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Amide Internucleoside Linkages Suppress the MicroRNA-like Off-Target Activity of Short Interfering RNA

ABSTRACT: RNA interference (RNAi) has rapidly matured as a novel therapeutic approach. In this field, chemical modifications have been critical to the clinical success of short interfering RNAs (siRNAs). Notwithstanding the significant advances, achieving robust durability and gene silencing in extrahepatic tissues, as well as reducing off-target effects of siRNA, are areas where chemical modifications can still improve siRNA performance. The present study developed the challenging synthesis of amide-linked guanosine dimers (GAM1G and GAM1A) and completed an "amide walk" one by one, systematically replacing every internucleoside phosphate with an amide linkage in a guide strand targeting the PIK3CB gene. Dual-luciferase and RT-qPCR assays in HeLa cells showed that, in a model system of unmodified siRNAs, the amide linkage at position 3 (between nucleosides 3 and 4) suppressed the cleavage of off-target YY1 and FADD mRNAs similarly to the industry gold standard modification glycol nucleic acid (GNA). These results suggest that amide linkages in the seed region have strong potential to improve the specificity of siRNAs by suppressing the microRNA-like off-target activity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE347548 | GEO | 2026/09/21

REPOSITORIES: GEO

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