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

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...

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Detalles Bibliográficos
Autores principales: Fang, Ziyuan, Dantsu, Yuliya, Chen, Cen, Zhang, Wen, Huang, Zhen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10187239/
https://www.ncbi.nlm.nih.gov/pubmed/37205589
http://dx.doi.org/10.1101/2023.05.02.539140
Descripción
Sumario: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 oligonucleotides (Se-ASO).