Advances in the Synthesis and Antisense Technology Applications of Bridged Nucleic Acid Monomers

Abstract

: Bridged Nucleic Acids (BNA) or Locked Nucleic Acids (LNA) belong to a class of nucleic acid modification that is obtained by connecting the 2'-O and 4'-C of ribose sugar using a methylene bridge. This ‘bridging or locking’ of ribose sugar has a tremendous impact on the biological and biophysical properties of therapeutic nucleic acids. They have enhanced stability against nucleases and also have a higher binding affinity for the target RNA. Owing to these advantages, BNA is one of the most preferred nucleic acids modifications of antisense oligonucleotides (ASOs). However, the synthesis of BNA monomers is lengthy and low-yielding and requires extensive protection and deprotection of the sugar functionalities. In this article, we aim to review challenges associated with their synthesis and discuss recent chemical, chemo-enzymatic, and transglycosylation strategies employed for the efficient and cost-effective synthesis of BNA monomers and selected BNA analogues.