Covalently attached intercalators restore duplex stability and splice-switching activity to triazole-modified oligonucleotides

Oligonucleotides are rapidly emerging as powerful therapeutics for hard to treat diseases. Short single-stranded oligonucleotides can base pair with target RNA and alter gene expression, providing an attractive therapeutic approach at the genetic level. Whilst conceptually appealing, oligonucleotides require chemical modification for clinical use. One emerging approach is to substitute the phosphodiester backbone with other chemical linkages such as triazole. The triazole linkage is inherently resistant to enzymatic degradation, providing stability in vivo, and is uncharged, potentially improving cell-penetration and in vivo distribution. Triazole linkages, however, are known to reduce RNA target binding affinity. Here we show that by attaching pyrene or anthraquinone to the ribose sugar on the 5 '-side of the triazole, it is possible to recover duplex stability and restore the splice switching ability of triazole-containing oligonucleotides.

Automated summary

Oligonucleotides are powerful therapeutics for difficult diseases, but they require chemical modification. Substituting the phosphodiester backbone with a triazole linkage provides stability and improved cell penetration, but reduces RNA target binding. Attaching pyrene or anthraquinone to the ribose sugar of the triazole restores stability and splice switching ability.