Development of Novel Bridged Nucleic Acids for Oligonucleotide Therapeutics

Oligonucleotide therapeutics have recently emerged as an important modality in drug discovery. The use of artificial nucleic acids is essential for improving both nuclease stability and duplex-forming ability. We previously demonstrated that oligonucleotides incorporating 2′-O,4′-C-methylene-bridged nucleic acid (2′,4′-BNA) exhibit high duplex-forming ability toward complementary RNA. In recent years, we have developed several novel bridged nucleic acids, including 2′-O,4′-C-spirocyclopropylene-bridged nucleic acid (scpBNA), 2′-O,4′-C-spirocyclopentylene-bridged nucleic acid (scpBNA2), and alkyl-substituted guanidine-bridged nucleic acids (GuNA [R]). These analogs provide RNA-binding affinity comparable to or greater than that of 2′,4′-BNA, while dramatically enhancing resistance to nuclease degradation. In particular, scpBNA and scpBNA2 were found to reduce the hepatotoxicity of antisense oligonucleotides. These artificial nucleic acids are expected to contribute to the development of highly potent and safer oligonucleotide therapeutics.