Synthesis and properties of fully-modified 4′-selenoRNA, an endonuclease-resistant RNA analog

• Published in: Bioorganic & medicinal chemistry 2022-12, Vol.76, p.117093-117093, Article 117093
• Main Authors: Ota, Masashi, Takahashi, Hiromi, Nogi, Yuhei, Kagotani, Yuma, Saito-Tarashima, Noriko, Kondo, Jiro, Minakawa, Noriaki
• Format: Article
• Language: English
• Subjects: 4′-selenoribonucleoside; 4′-selenoRNA; Endonucleases; modified RNA; Nuclease resistance; RNA; siRNA; X-ray analysis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2022.117093

[Display omitted] A large number of chemically modified oligonucleotides (ONs) have been developed for RNA-based technologies. In most modified RNAs, the characteristic 2′-hydroxyl (2′-OH) groups are removed to enhance both nuclease resistance and hybridization ability. However, the importance of the 2′-OH group in RNA structure and function is well known. Here, we report the synthesis and properties of 4′-selenoRNA in which all four nucleoside units retain the 2′-OH groups but contain a selenium atom instead of an oxygen atom at the 4′-position of the furanose ring. 4′-SelenoRNA has enhanced ability to form duplexes with RNA, and high endonuclease resistance despite the presence of the 2′-OH groups. X-ray crystallography analysis showed that the 4′-selenoRNA duplex adopts an A-conformation, similar to natural RNA, although one 4′-selenocytidine residue has unusual South-type sugar puckering. Furthermore, preliminary studies using 4′-seleno-modified siRNAs suggest that 4′-selenoRNA may be applicable to RNA interference technology. Collectively, our results raise the possibility of a new class of modified RNA in which 2′-OH groups do not need to be masked.