Backbone extension by methylene insertion as a strategy to restore duplex stability of sulfonamide-linked oligodeoxynucleotides while preserving RNase H activity

Org Biomol Chem. 2026 May 13;24(18):3863-3867. doi: 10.1039/d6ob00490c.

Abstract

A backbone-extended sulfonamide nucleic acid was developed for use in gapmer antisense oligonucleotides. Backbone extension restores duplex stability while preserving the ability of the oligonucleotides to induce RNase H-mediated RNA cleavage. Structural analysis suggests that the extended linkage adopts unusual backbone conformations yet remains compatible with canonical A-type duplex formation, highlighting backbone extension as a new design parameter for antisense oligonucleotide therapeutics.

MeSH terms

  • Nucleic Acid Conformation
  • Oligodeoxyribonucleotides* / chemistry
  • Oligodeoxyribonucleotides* / metabolism
  • Oligonucleotides, Antisense / chemistry
  • Ribonuclease H* / chemistry
  • Ribonuclease H* / metabolism
  • Sulfonamides* / chemistry

Substances

  • Ribonuclease H
  • Sulfonamides
  • Oligodeoxyribonucleotides
  • Oligonucleotides, Antisense