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Effective gene silencing activity of prodrug-type 2′-O-methyldithiomethyl siRNA compared with non-prodrug-type 2′-O-methyl siRNA

2018; Elsevier BV; Volume: 28; Issue: 12 Linguagem: Inglês

10.1016/j.bmcl.2018.05.016

1464-3405

Junsuke Hayashi, Misa Nishigaki, Yosuke Ochi, Shun‐ichi Wada, Fumito Wada, Osamu Nakagawa, Satoshi Obika, Mariko Harada‐Shiba, Hidehito Urata,

MicroRNA in disease regulation

Small interfering RNAs (siRNAs) are an active agent to induce gene silencing and they have been studied for becoming a biological and therapeutic tool. Various 2′-O-modified RNAs have been extensively studied to improve the nuclease resistance. However, the 2′-O-modified siRNA activities were often decreased by modification, since the bulky 2′-O-modifications inhibit to form a RNA-induced silencing complex (RISC). We developed novel prodrug-type 2′-O-methyldithiomethyl (MDTM) siRNA, which is converted into natural siRNA in an intracellular reducing environment. Prodrug-type 2′-O-MDTM siRNAs modified at the 5′-end side including 5′-end nucleotide and the seed region of the antisense strand exhibited much stronger gene silencing effect than non-prodrug-type 2′-O-methyl (2′-O-Me) siRNAs. Furthermore, the resistances for nuclease digestion of siRNAs were actually enhanced by 2′-O-MDTM modifications. Our results indicate that 2′-O-MDTM modifications improve the stability of siRNA in serum and they are able to be introduced at any positions of siRNA.