Mikutis, SigitasRebelo, MariaYankova, ElizaGu, MuxinTang, CongCoelho, Ana R.Yang, MoHazemi, Madoka E.Pires de Miranda, MartaEleftheriou, MariaRobertson, MaxVassiliou, George S.Adams, David J.Simas, J. PedroCorzana, FranciscoSchneekloth, John S.Tzelepis, KonstantinosBernardes, Gonçalo J.L.2023-05-172023-05-172023-05-242374-7943http://hdl.handle.net/10400.14/41145Nature 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 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.engProximity-Induced Nucleic Acid Degrader (PINAD) approach to targeted RNA degradation using small moleculesjournal article10.1021/acscentsci.3c0001585156240026PMC1021451237252343000981755900001