Synthesis and therapeutic applications of oligonucleotides containing 2'-o,4'-c-ethylene-and 3'-o,4'-c-propylene-bridged nucleotides

Abstract

Recently, bridged nucleic acids have come to be more utilized as one of the promising components of therapeutic oligonucleotides. Oligonucleotides containing 2'-O,4'-C-ethylene-bridged nucleic acid (ENA) have been synthesized as functional oligonucleotides to further optimize the 2'-O,4'-C-methylene-linkage of bridged nucleic acids (2',4'-BNA) or locked nucleic acids (LNA). Oligonucleotides containing ENA residues show three notable properties: (i) a high affinity to complementary single-stranded RNA to form duplexes, (ii) a triplex formation with double-stranded DNA, and (iii) a dramatically high resistance compared to 2',4'-BNA/LNA against exonucleases and endonucleases. On the basis of these properties, ENA-modified oligonucleotides are currently being developed as therapeutics of genetic disorders such as Duchenne muscular dystrophy (DMD). On the other hand, a modified nucleotide containing 3'-O,4'-C-propylene linkage can be incorporated into the third position of 2',5'-oligoadenylate (2-5A) to maintain biological activities with nuclease resistance. This modified 2-5A with 3'-O,4'-C-propylene adenosine could be useful for novel anti-cancer and anti-viral reagents as an RNase L activator.