Development of Synthetic Routes to 2'-O,4'-C-Spirocyclopentylene-Bridged Nucleic Acids: Thymidine, Guanosine, and Adenosine.

ABSTRACT: Modified nucleic acids are crucial for improving the efficacy and safety of antisense oligonucleotides (ASOs). We previously synthesized and evaluated 2'-O,4'-C-spirocyclopentylene-bridged nucleic acid (scpBNA2) bearing the pyrimidine nucleobases thymine (T) and 5-methylcytosine (^mC). Oligonucleotides incorporating scpBNA2 exhibited strong binding affinity toward complementary single-stranded RNA (ssRNA) and high resistance to nuclease degradation. These favorable properties enabled ASOs containing scpBNA2-T and scpBNA2-^mC in the wing regions to induce potent target RNA knockdown both in vitro and in vivo. Furthermore, replacing 2'-O,4'-C-methylene-bridged nucleic acid/locked nucleic acid (2',4'-BNA/LNA) with scpBNA2 significantly reduced hepatotoxicity, underscoring

SUBMITTER: Kumagai R 

PROVIDER: S-EPMC12712746 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature