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

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

  • ACS Cent Sci. 2023 Apr 26;9(5):892-904. doi: 10.1021/acscentsci.3c00015.
Sigitas Mikutis 1,  Maria Rebelo 2,  Eliza Yankova 3 4,  Muxin Gu 3,  Cong Tang 2,  Ana R Coelho 2,  Mo Yang 5,  Madoka E Hazemi 1,  Marta Pires de Miranda 2,  Maria Eleftheriou 3 4,  Max Robertson 1,  George S Vassiliou 3,  David J Adams 6,  J Pedro Simas 2 7,  Francisco Corzana 8,  John S Schneekloth Jr 5,  Konstantinos Tzelepis 3 4,  Gonçalo J L Bernardes 1 2
Affiliations

Affiliations

  • 1 Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
  • 2 Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028, Lisboa, Portugal.
  • 3 Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, U.K.
  • 4 Milner Therapeutics Institute, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, U.K.
  • 5 Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States.
  • 6 Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, U.K.
  • 7 Católica Biomedical Research and Católica Medical School, Universidade Católica Portuguesa, 1649-023 Lisboa, Portugal.
  • 8 Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de La Rioja, 26006 Logroño, Spain.
PMID: 37252343 DOI: 10.1021/acscentsci.3c00015
Abstract

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.

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