Proximity-Induced Nucleic Acid Degrader (PINAD) Approach to Targeted RNA Degradation Using Small Molecules
| العنوان: | Proximity-Induced Nucleic Acid Degrader (PINAD) Approach to Targeted RNA Degradation Using Small Molecules |
|---|---|
| المؤلفون: | Mikutis, Sigitas, Rebelo, Maria, Yankova, Eliza, Gu, Muxin, Tang, Cong, Coelho, Ana R, Yang, Mo, Hazemi, Madoka E., Pires de Miranda, Marta, Eleftheriou, Maria, Robertson, Max, Vassiliou, George S., Adams, David J., Simas, J Pedro, Corzana, Francisco, Schneekloth, John S., Tzelepis, Konstantinos, Bernardes, Gonçalo J. L. |
| المساهمون: | Corzana, Francisco [0000-0001-5597-8127], Tzelepis, Konstantinos [0000-0002-4865-7648], Bernardes, Gonçalo JL [0000-0001-6594-8917], Apollo - University of Cambridge Repository, Veritati - Repositório Institucional da Universidade Católica Portuguesa, Repositório da Universidade de Lisboa |
| بيانات النشر: | American Chemical Society (ACS), 2023. |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | 34 Chemical Sciences, General Chemical Engineering, Prevention, 3 Good Health and Well Being, General Chemistry, Vaccine Related, Rare Diseases, Orphan Drug, Emerging Infectious Diseases, 5.1 Pharmaceuticals, Biodefense, Genetics, 3404 Medicinal and Biomolecular Chemistry, 5 Development of treatments and therapeutic interventions |
| الوصف: | Copyright © 2023 The Authors. Published by American Chemical Society 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 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. We thank UKRI (BBSRC DTP scholarship to S.M.), the Jardine Foundation and Cambridge Trust (PhD scholarship to M.E.H.), the Agencia Estatal de Investigación (AEI; grant PID2021-127622OB-I00 to F.C.), the Wellcome Trust (grants RG94424, RG83195, G106133, to K.T. and E.Y.), UKRI Medical Research Council (grant RG83195 to K.T. and E.Y.), Leukaemia UK (grant G108148 to K.T and M.E.), National Institutes of Health (Intramural Research Program, project number Z01 BC011585 07 to J.S.S. Jr.) and the Cancer Research UK (Senior Cancer Fellowship, grant no. C22324/A23015 to G.S.V.). |
| وصف الملف: | application/pdf |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4ca9e265512ad2e28835f2cae732bdf9Test https://www.repository.cam.ac.uk/handle/1810/350040Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....4ca9e265512ad2e28835f2cae732bdf9 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |