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

Autor:	Mikutis S; Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K., Rebelo M; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028, Lisboa, Portugal., Yankova E; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, U.K.; Milner Therapeutics Institute, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, U.K., Gu M; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, U.K., Tang C; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028, Lisboa, Portugal., Coelho AR; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028, Lisboa, Portugal., Yang M; Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States., Hazemi ME; Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K., Pires de Miranda M; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028, Lisboa, Portugal., Eleftheriou M; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, U.K.; Milner Therapeutics Institute, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, U.K., Robertson M; Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K., Vassiliou GS; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, U.K., Adams DJ; Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, U.K., Simas JP; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028, Lisboa, Portugal.; Católica Biomedical Research and Católica Medical School, Universidade Católica Portuguesa, 1649-023 Lisboa, Portugal., Corzana F; Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de La Rioja, 26006 Logroño, Spain., Schneekloth JS Jr; Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States., Tzelepis K; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, U.K.; Milner Therapeutics Institute, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, U.K., Bernardes GJL; Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028, Lisboa, Portugal.
Jazyk:	angličtina
Zdroj:	ACS central science [ACS Cent Sci] 2023 Apr 26; Vol. 9 (5), pp. 892-904. Date of Electronic Publication: 2023 Apr 26 (Print Publication: 2023).
DOI:	10.1021/acscentsci.3c00015
Abstrakt:	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. Competing Interests: The authors declare the following competing financial interest(s): S.M., M.H., K.T. and G.J.L.B. are co-inventors on a patent application (ref. PCT/EP2021/072517, filed on 12th August 2021) that describes methods for nucleic acid cleavage. S.M. and G.B. are co-inventors on a patent application (ref. PCT/EP2022/080220, filled on 28th October 2022) that describes methods for nucleic acid cleavage. All other authors declare no conflict of interests. (© 2023 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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