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

Ziyuan FangYuliya DantsuCen ChenWen ZhangZhen Huang
Published in: bioRxiv : the preprint server for biology (2023)
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 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 oli-gonucleotides (Se-ASO).
Keyphrases
  • nucleic acid
  • high resolution
  • dna binding
  • magnetic resonance imaging
  • mass spectrometry
  • transcription factor
  • computed tomography
  • magnetic resonance
  • anaerobic digestion
  • risk assessment
  • binding protein