Proximity-Induced Nucleic Acid Degrader (PINAD) Approach to Targeted RNA Degradation Using Small Molecules

Nature has evolved intricate machinery to target and degrade RNA, and some of these molecular mechanisms can be adapted for therapeutic use. Small interfering RNAs and RNase H-inducing oligonucleo-tides have yielded therapeutic agents against diseases that cannot be tackled using protein-centered approaches. Because these therapeutic agents are nucleic acid-based, they have several inherent drawbacks which include poor cellular uptake and stability. Here we report a new approach to target and degrade RNA using small molecules, proximity-induced nucleic acid degrader (PINAD). We have utilized this strategy to design two families of RNA degraders which target two different RNA structures within the genome of SARS-CoV-2: G-quadruplexes and the betacoronaviral pseudoknot. We demonstrate that these novel molecules degrade their targets using in vitro, in cellulo, and in vivo SARS-CoV-2 infection models. Our strategy allows any RNA binding small molecule to be converted into a degrader, empowering RNA binders that are not potent enough to exert a phenotypic effect on their own. PINAD raises the possibility of targeting and destroying any disease-related RNA species, which can greatly expand the space of druggable targets and diseases.

Automated summary

Researchers report a new approach called proximity-induced nucleic acid degrader (PINAD) to target and degrade RNA using small molecules. They have designed two families of RNA degraders that target two different RNA structures in SARS-CoV-2: G-quadruplexes and the betacoronaviral pseudoknot. These novel molecules have been shown to degrade their targets in vitro, in cellulo, and in vivo SARS-CoV-2 infection models. PINAD enables the conversion of any RNA binding small molecule into a degrader, potentially expanding the space of druggable targets and diseases by targeting and destroying disease-related RNA species.