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bioRxiv · 10.1101/2023.05.02.539140

Syntheses of Pyrimidine-Modified Seleno-DNAs as Stable Antisense Molecules

Fang, Z.·Dantsu, Y.·Chen, C.·Zhang, W.·Huang, Z.
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Abstract

Chemically 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 ASOs 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 didnt 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 oli-gonucleotides (Se-ASO).

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Fang, Z., Dantsu, Y., Chen, C., Zhang, W., Huang, Z.. 2023-05-02. Syntheses of Pyrimidine-Modified Seleno-DNAs as Stable Antisense Molecules. https://doi.org/10.1101/2023.05.02.539140

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