Synthesis and characterization of 4′-C-guanidinomethyl-2′-O-methyl-modified RNA oligomers

Abstract

This study investigated the synthesis and properties of 4′-C-guanidinomethyl-2′-O-methyluridine and RNAs containing the analog. Thermal and thermodynamic stabilities of double-stranded RNAs (dsRNAs) containing the nucleoside analog were examined. It was found that although the analog decreased the thermal and thermodynamic stabilities of dsRNA, it had base-discrimination ability. The 4′-C-guanidinomethyl modification increased stability of RNAs in a buffer containing serum. Furthermore, small interference RNAs incorporating one analog at the passenger strand still preserved their RNA interference activities. It was suggested that the 4′-guanidinomethyl modification significantly improved cell membrane permeability of RNA. Thus, 4′-C-guanidinomethyl-2′-O-methyl analogs may be useful in improving the properties of therapeutic siRNA molecules.

Keywords:

• RNA interference
• small interfering RNA
• 4′-guanidinomethyl group
• thermal stability
• nuclease resistance
• cell membrane permeability

Acknowledgment

The authors thank Professor Yoko Hirata (Gifu University) for supplying cells and giving technical advice.

Additional information

Funding

This work was supported by the Japan Agency for Medical Research and Development (AMED) through its Funding Program for Basic Science and Platform Technology Program for Innovative Biological Medicine, development of siRNA conjugates with tissue-specific delivery functions (18am0301022h0004).