Properties of Stereopure Phosphorothioate Groups in RNA-PROTACs

Abstract

Proteolysis-targeting chimeras (PROTACs) are an emerging therapeutic modality that enable the degradation of target proteins via the endogenous ubiquitin–proteasome pathway. We are applying this concept to the degradation of RNA-binding proteins (RBPs), which often lack drug-like binding pockets for small molecules. When targeting RBPs with RNA-PROTACs, the targeting ligand consists of short, chemically modified oligoribonucleotides that are iso-sequential with endogenous RNA consensus sequences. Specifically, we are investigating the phosphorothioate (PS) backbone, in which a sulfur atom replaces a non-bridging oxygen in the RNA phosphodiester linkage. PS modifications enhance stability against nucleases, but introduce chirality at the phosphorus atom, when introduced using conventional synthesis reagents, generating diastereoisomers whose stereochemistry can significantly enhance RNA–protein interactions.