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 oligonucleotides
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 usingin vitro,in cellulo, andin vivoSARS-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.