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Proximity-Induced Nucleic Acid Degrader (PINAD) approach to targeted RNA degradation using small molecules

2023Artigo científico Acesso aberto
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dc.contributor.authorMikutis, Sigitas
dc.contributor.authorRebelo, Maria
dc.contributor.authorYankova, Eliza
dc.contributor.authorGu, Muxin
dc.contributor.authorTang, Cong
dc.contributor.authorCoelho, Ana R
dc.contributor.authorYang, Mo
dc.contributor.authorHazemi, Madoka E.
dc.contributor.authorPires de Miranda, Marta
dc.contributor.authorEleftheriou, Maria
dc.contributor.authorRobertson, Max
dc.contributor.authorVassiliou, George S.
dc.contributor.authorAdams, David J.
dc.contributor.authorSimas, J Pedro
dc.contributor.authorCorzana, Francisco
dc.contributor.authorSchneekloth, John S.
dc.contributor.authorTzelepis, Konstantinos
dc.contributor.authorBernardes, Gonçalo J. L.
dc.date.accessioned2023-06-07T13:42:12Z
dc.date.available2023-06-07T13:42:12Z
dc.date.issued2023
dc.descriptionCopyright © 2023 The Authors. Published by American Chemical Societypt_PT
dc.description.abstractNature 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.pt_PT
dc.description.sponsorshipWe 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.).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationACS Cent Sci. 2023 Apr 26;9(5):892-904pt_PT
dc.identifier.doi10.1021/acscentsci.3c00015pt_PT
dc.identifier.eissn2374-7951
dc.identifier.issn2374-7943
dc.identifier.urihttp://hdl.handle.net/10451/58041
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherACS Publicationspt_PT
dc.relation.publisherversionhttps://pubs.acs.org/journal/acsciipt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleProximity-Induced Nucleic Acid Degrader (PINAD) approach to targeted RNA degradation using small moleculespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage904pt_PT
oaire.citation.issue5pt_PT
oaire.citation.startPage892pt_PT
oaire.citation.titleACS Central Sciencept_PT
oaire.citation.volume9pt_PT
person.familyNameSousa Rebelo
person.familyNameTang
person.familyNameCoelho
person.familyNamePires de Miranda
person.familyNameSimas
person.familyNameBernardes
person.givenNameMaria
person.givenNameCong
person.givenNameAna
person.givenNameMarta
person.givenNameJ Pedro
person.givenNameGonçalo
person.identifier.ciencia-id8B1D-62C4-0050
person.identifier.ciencia-id6213-029E-F967
person.identifier.ciencia-id2314-E49D-3FF9
person.identifier.ciencia-id8A1D-8B1A-205B
person.identifier.ciencia-id3513-BF02-52B7
person.identifier.orcid0000-0003-2715-7182
person.identifier.orcid0000-0003-1661-6793
person.identifier.orcid0000-0002-0965-7573
person.identifier.orcid0000-0003-3733-4963
person.identifier.orcid0000-0001-6982-9253
person.identifier.orcid0000-0001-6594-8917
person.identifier.scopus-author-id56404089400
person.identifier.scopus-author-id7003457329
person.identifier.scopus-author-id14046757500
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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