Synthesis, Stability, and Anti-Tumour Activity of a New Category of "Stapled" Antisense Oligonucleotides with Stimuli-Responsive Feature

J Pharm Sci. 2021 Sep;110(9):3166-3170. doi: 10.1016/j.xphs.2021.05.024. Epub 2021 Jun 6.


The development of nucleic acid drugs with unique structures and mechanisms has stimulated great research interest. Herein, we report a general strategy to construct "stapled" structures of single-stranded antisense oligonucleotides (ASONs) with a stimuli-responsive feature. "Stapled" cyclic structures can be synthesized with reactive bifunctional handles that react with thiol groups of phosphorothioate (PS)-modified ASONs, and can be alternatively adjusted depending on the desired PS sites in the ASON strand. The disulphide group in the stapled handle can be cleaved in the reducing microenvironment of tumour cells. Thus, "stapled" ASONs may be transformed back to a linear conformation to facilitate binding to target mRNAs. Stapling conferred protection against degradation, and enhanced anti-tumour activity compared to linear counterparts. This study provides a new, effective, and convenient strategy for designing ASONs with "stapled" structures, and also adds a further contribution to facilitate the stability and biological efficacy of novel nucleic acid-based therapeutics.

Keywords: Anti-tumour activity; Antisense oligonucleotides; Stability; Stapled DNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Neoplasms* / drug therapy
  • Oligonucleotides, Antisense*
  • RNA, Messenger
  • Tumor Microenvironment


  • Oligonucleotides, Antisense
  • RNA, Messenger