Synthesis of Pyrimidine Modified Seleno‐DNA as a Novel Approach to Antisense Candidate

Abstract

AbstractChemically modified antisense oligonucleotides (ASO) currently in pre‐clinical and clinical experiments mainly focus on the 2′‐position derivatizations to enhance stability and targeting affinity. Considering the possible incompatibility of 2′‐modifications with RNase H stimulation and activity, we have hypothesized that the atom specific modifications on nucleobases can retain the complex structure and RNase H activity, while enhancing ASO's binding affinity, specificity, and stability against nucleases. Herein we report a novel strategy to explore our hypothesis by synthesizing the deoxynucleoside phosphoramidite building block with the seleno‐modification at 5‐position of thymidine, as well as its Se‐oligonucleotides. Via X‐ray crystal structural study, we found that the Se‐modification was located in the major groove of nucleic acid duplex and didn't cause the thermal and structural perturbations. Surprisingly, our nucleobase‐modified Se‐DNAs were exceptionally resistant to nuclease digestion, while compatible with RNase H activity. This affords a novel avenue for potential anti‐sense modification in the form of Se‐antisense oligonucleotides (Se‐ASO).