RNA bioisosteres: Chemistry and properties of 4'-thioRNA and 4'-selenoRNA

Abstract

The design and synthesis of nucleic acid-based therapeutics is one of the most promising approaches to drug development and disease therapy. In order to develop agents with improved nuclease resistance and hybridization ability, a large number of chemically modified oligonucleotides (ONs), especially RNA analogs, have been designed and prepared. However, this has led to ONs with overly complex structures, resulting in a lack of biocompatibility with natural RNA. With this in mind, 4'-thioRNA, which has a sulfur atom in place of the furanose ring oxygen, was proposed as a natural RNA bioisostere. The building blocks for 4'-thioRNA, i.e., 4'-thioribonucleosides, were prepared stereoselectively via the Pummerer reaction between a silylated nucleobase and the corresponding sulfoxide, which was obtained from a 4-thiosugar. The resulting 4'-thioRNA exhibited sufficient hybridization ability and nuclease resistance, as well as biocompatibility with natural RNA, and was used effectively as a chemically modified siRNA and for isolation of 4'-thioRNA aptamers. Current progress in the development of a new RNA bioisostere 4'-selenoRNA, which contains a selenium atom, is also described.