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

ABSTRACT: 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.

SUBMITTER: Dysko A 

PROVIDER: S-EPMC9175110 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature