RNase H-sensitive multifunctional ASO-based constructs as promising tools for the treatment of multifactorial complex pathologies

Combined therapies play a key role in the fight against complex pathologies, such as cancer and related drug-resistance issues. This is particularly relevant in targeted therapies where inhibition of the drug target can be overcome by cross-activating complementary pathways. Unfortunately, the drug...

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Autores: Mata Ventosa, Aida, Vila Planas, Ariadna, Solsona Pujol, Aina, Dueña Pascuet, Jordi de la, Torrents, Maria, Izquierdo García, Eduardo, Pastor Anglada, Marçal, Pérez Torras, Sandra, Terrazas Martínez, Montserrat
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2024
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositório:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/225206
Acesso em linha:https://hdl.handle.net/2445/225206
Access Level:Acceso aberto
Palavra-chave:Ribonucleases
Proteïnes recombinants
Recombinant proteins
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spelling RNase H-sensitive multifunctional ASO-based constructs as promising tools for the treatment of multifactorial complex pathologiesMata Ventosa, AidaVila Planas, AriadnaSolsona Pujol, AinaDueña Pascuet, Jordi de laTorrents, MariaIzquierdo García, EduardoPastor Anglada, MarçalPérez Torras, SandraTerrazas Martínez, MontserratRibonucleasesProteïnes recombinantsRibonucleasesRecombinant proteinsCombined therapies play a key role in the fight against complex pathologies, such as cancer and related drug-resistance issues. This is particularly relevant in targeted therapies where inhibition of the drug target can be overcome by cross-activating complementary pathways. Unfortunately, the drug combinations approved to date –mostly based on small molecules– face several problems such as toxicity effects, which limit their clinical use. To address these issues, we have designed a new class of RNase H-sensitive construct (3ASO) that can be disassembled intracellularly upon cell entry, leading to the simultaneous release of three different therapeutic oligonucleotides (ONs), tackling each of them the mRNA of a different protein. Here, we used Escherichia coli RNase H1 as a model to study an unprecedented mode of recognition and cleavage, that is mainly dictated by the topology of our RNA·DNA-based hybrid construct. As a model system for our technology we have created 3ASO constructs designed to specifically inhibit the expression of HER2, Akt and Hsp27 in HER2+ breast cancer cells. These trifunctional ON tools displayed very low toxicity and good levels of antiproliferative activity in HER2+ breast cancer cells. The present study will be of great potential in the fight against complex pathologies involving multiple mRNA targets, as the proposed cleavable designs will allow the efficient single-dose administration of different ON drugs simultaneously.Elsevier2026202620242026info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion11 p.application/pdfhttps://hdl.handle.net/2445/225206Articles publicats en revistes (Química Inorgànica i Orgànica)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1016/j.bioorg.2024.107595Bioorganic Chemistry, 2024, vol. 150https://doi.org/10.1016/j.bioorg.2024.107595cc-by-nc (c) Mata Ventosa, Aida et al., 2024http://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/2252062026-05-29T05:05:01Z
dc.title.none.fl_str_mv RNase H-sensitive multifunctional ASO-based constructs as promising tools for the treatment of multifactorial complex pathologies
title RNase H-sensitive multifunctional ASO-based constructs as promising tools for the treatment of multifactorial complex pathologies
spellingShingle RNase H-sensitive multifunctional ASO-based constructs as promising tools for the treatment of multifactorial complex pathologies
Mata Ventosa, Aida
Ribonucleases
Proteïnes recombinants
Ribonucleases
Recombinant proteins
title_short RNase H-sensitive multifunctional ASO-based constructs as promising tools for the treatment of multifactorial complex pathologies
title_full RNase H-sensitive multifunctional ASO-based constructs as promising tools for the treatment of multifactorial complex pathologies
title_fullStr RNase H-sensitive multifunctional ASO-based constructs as promising tools for the treatment of multifactorial complex pathologies
title_full_unstemmed RNase H-sensitive multifunctional ASO-based constructs as promising tools for the treatment of multifactorial complex pathologies
title_sort RNase H-sensitive multifunctional ASO-based constructs as promising tools for the treatment of multifactorial complex pathologies
dc.creator.none.fl_str_mv Mata Ventosa, Aida
Vila Planas, Ariadna
Solsona Pujol, Aina
Dueña Pascuet, Jordi de la
Torrents, Maria
Izquierdo García, Eduardo
Pastor Anglada, Marçal
Pérez Torras, Sandra
Terrazas Martínez, Montserrat
author Mata Ventosa, Aida
author_facet Mata Ventosa, Aida
Vila Planas, Ariadna
Solsona Pujol, Aina
Dueña Pascuet, Jordi de la
Torrents, Maria
Izquierdo García, Eduardo
Pastor Anglada, Marçal
Pérez Torras, Sandra
Terrazas Martínez, Montserrat
author_role author
author2 Vila Planas, Ariadna
Solsona Pujol, Aina
Dueña Pascuet, Jordi de la
Torrents, Maria
Izquierdo García, Eduardo
Pastor Anglada, Marçal
Pérez Torras, Sandra
Terrazas Martínez, Montserrat
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Ribonucleases
Proteïnes recombinants
Ribonucleases
Recombinant proteins
topic Ribonucleases
Proteïnes recombinants
Ribonucleases
Recombinant proteins
description Combined therapies play a key role in the fight against complex pathologies, such as cancer and related drug-resistance issues. This is particularly relevant in targeted therapies where inhibition of the drug target can be overcome by cross-activating complementary pathways. Unfortunately, the drug combinations approved to date –mostly based on small molecules– face several problems such as toxicity effects, which limit their clinical use. To address these issues, we have designed a new class of RNase H-sensitive construct (3ASO) that can be disassembled intracellularly upon cell entry, leading to the simultaneous release of three different therapeutic oligonucleotides (ONs), tackling each of them the mRNA of a different protein. Here, we used Escherichia coli RNase H1 as a model to study an unprecedented mode of recognition and cleavage, that is mainly dictated by the topology of our RNA·DNA-based hybrid construct. As a model system for our technology we have created 3ASO constructs designed to specifically inhibit the expression of HER2, Akt and Hsp27 in HER2+ breast cancer cells. These trifunctional ON tools displayed very low toxicity and good levels of antiproliferative activity in HER2+ breast cancer cells. The present study will be of great potential in the fight against complex pathologies involving multiple mRNA targets, as the proposed cleavable designs will allow the efficient single-dose administration of different ON drugs simultaneously.
publishDate 2024
dc.date.none.fl_str_mv 2024
2026
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/225206
url https://hdl.handle.net/2445/225206
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.bioorg.2024.107595
Bioorganic Chemistry, 2024, vol. 150
https://doi.org/10.1016/j.bioorg.2024.107595
dc.rights.none.fl_str_mv cc-by-nc (c) Mata Ventosa, Aida et al., 2024
http://creativecommons.org/licenses/by-nc/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc (c) Mata Ventosa, Aida et al., 2024
http://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 11 p.
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv Articles publicats en revistes (Química Inorgànica i Orgànica)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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