Proximity-Induced Nucleic Acid Degrader (PINAD) approach to targeted RNA degradation using small molecules
Autor(a) principal: | |
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Data de Publicação: | 2023 |
Outros Autores: | , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.14/41145 |
Resumo: | 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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Proximity-Induced Nucleic Acid Degrader (PINAD) approach to targeted RNA degradation using small moleculesNature 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.Veritati - Repositório Institucional da Universidade Católica PortuguesaMikutis, 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.2023-05-17T08:17:27Z2023-05-242023-05-24T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.14/41145eng2374-794310.1021/acscentsci.3c0001585156240026info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-25T01:39:11Zoai:repositorio.ucp.pt:10400.14/41145Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:33:49.133118Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Proximity-Induced Nucleic Acid Degrader (PINAD) approach to targeted RNA degradation using small molecules |
title |
Proximity-Induced Nucleic Acid Degrader (PINAD) approach to targeted RNA degradation using small molecules |
spellingShingle |
Proximity-Induced Nucleic Acid Degrader (PINAD) approach to targeted RNA degradation using small molecules Mikutis, Sigitas |
title_short |
Proximity-Induced Nucleic Acid Degrader (PINAD) approach to targeted RNA degradation using small molecules |
title_full |
Proximity-Induced Nucleic Acid Degrader (PINAD) approach to targeted RNA degradation using small molecules |
title_fullStr |
Proximity-Induced Nucleic Acid Degrader (PINAD) approach to targeted RNA degradation using small molecules |
title_full_unstemmed |
Proximity-Induced Nucleic Acid Degrader (PINAD) approach to targeted RNA degradation using small molecules |
title_sort |
Proximity-Induced Nucleic Acid Degrader (PINAD) approach to targeted RNA degradation using small molecules |
author |
Mikutis, Sigitas |
author_facet |
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. |
author_role |
author |
author2 |
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. |
author2_role |
author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Veritati - Repositório Institucional da Universidade Católica Portuguesa |
dc.contributor.author.fl_str_mv |
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. |
description |
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. |
publishDate |
2023 |
dc.date.none.fl_str_mv |
2023-05-17T08:17:27Z 2023-05-24 2023-05-24T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.14/41145 |
url |
http://hdl.handle.net/10400.14/41145 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
2374-7943 10.1021/acscentsci.3c00015 85156240026 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
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1799132064501465088 |