Fang, ZiyuanDantsu, YuliyaChen, CenZhang, WenHuang, Zhen2024-01-022024-01-022023-05-03Fang Z, Dantsu Y, Chen C, Zhang W, Huang Z. Syntheses of Pyrimidine-Modified Seleno-DNAs as Stable Antisense Molecules. Preprint. bioRxiv. 2023;2023.05.02.539140. Published 2023 May 3. doi:10.1101/2023.05.02.539140https://hdl.handle.net/1805/37527Chemically 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 antisense modification in the form of Se-antisense oligonucleotides (Se-ASO).en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalAntisense oligonucleotides (ASO)RNase H stimulationAntisense modificationArticle