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Keywords:

  • Oligonucleotides;
  • Antisense therapeutics;
  • Nucleic acids;
  • RNA;
  • BNA

Abstract

Among the multitude of chemical modifications that have been described over the past two decades, oligonucleotide analogs that are modified at the 2′-position of the furanose sugar have been especially useful for improving the drug-like properties of antisense oligonucleotides (ASOs). These modifications bias the sugar pucker towards the 3′-endo-conformation and improve ASO affinity for its biological target (i.e., mRNA). In addition, antisense drugs incorporating 2′-modified nucleotides exhibit enhanced metabolic stability, and improved pharmacokinetic and toxicological properties. Further conformational restriction of the 2′-substituent to the 4′-position of the furanose ring yielded the 2′,4′-bridged nucleic acid (BNA) analogs. ASOs containing BNA modifications showed unprecedented increase in binding affinity for target RNA, while also improved nuclease resistance, in vitro and in vivo potency. Several ASO drug candidates containing 2′-modified nucleotides have entered clinical trials and continue to make progress in the clinic for a variety of therapeutic indications.