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

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.