Controlled sulfur-based engineering confers mouldability to phosphorothioate antisense oligonucleotides

13 pags., 6 figs., 2 tabs.

Detalles Bibliográficos
Autores: Genna, Vito, Iglesias-Fernández, Javier, Reyes-Fraile, Laura, Villegas, Nuria, Guckian, Kevin, Seth, Punit, Wan, Brad, Cabrero Fernández, Cristina, Terrazas, Montserrat, Brun-Heath, Isabelle, González, Carlos, Sciabola, Simone, Villalobos, Anabella, Orozco, Modesto
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/343695
Acceso en línea:http://hdl.handle.net/10261/343695
https://api.elsevier.com/content/abstract/scopus_id/85162240719
Access Level:acceso abierto
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spelling Controlled sulfur-based engineering confers mouldability to phosphorothioate antisense oligonucleotidesGenna, VitoIglesias-Fernández, JavierReyes-Fraile, LauraVillegas, NuriaGuckian, KevinSeth, PunitWan, BradCabrero Fernández, CristinaTerrazas, MontserratBrun-Heath, IsabelleGonzález, CarlosSciabola, SimoneVillalobos, AnabellaOrozco, Modesto13 pags., 6 figs., 2 tabs.Phosphorothioates (PS) have proven their effectiveness in the area of therapeutic oligonucleotides with applications spanning from cancer treatment to neurodegenerative disorders. Initially, PS substitution was introduced for the antisense oligonucleotides (PS ASOs) because it confers an increased nuclease resistance meanwhile ameliorates cellular uptake and in-vivo bioavailability. Thus, PS oligonucleotides have been elevated to a fundamental asset in the realm of gene silencing therapeutic methodologies. But, despite their wide use, little is known on the possibly different structural changes PS-substitutions may provoke in DNA·RNA hybrids. Additionally, scarce information and significant controversy exists on the role of phosphorothioate chirality in modulating PS properties. Here, through comprehensive computational investigations and experimental measurements, we shed light on the impact of PS chirality in DNA-based antisense oligonucleotides; how the different phosphorothioate diastereomers impact DNA topology, stability and flexibility to ultimately disclose pro-Sp S and pro-Rp S roles at the catalytic core of DNA Exonuclease and Human Ribonuclease H; two major obstacles in ASOs-based therapies. Altogether, our results provide full-atom and mechanistic insights on the structural aberrations PS-substitutions provoke and explain the origin of nuclease resistance PS-linkages confer to DNA·RNA hybrids; crucial information to improve current ASOs-based therapies.European Molecular Biology Organization [EMBO, ALTF 103-2018]; Juan de la Cierva-INCORPORACION´ [IJC2019-040468-I]; Spanish Ministry of Science [RTI2018-096704-B-100, PID2020-116620GB-I00, PID2021- 122478NB-100]; Catalan Government AGAUR [SGR2017-134]; Instituto de Salud Carlos III–Instituto Nacional de Bioinformatica (ISCIII PT 17 ´ /0009/0007 co-funded by the Fondo Europeo de Desarrollo Regional); H2020 European Commission; ‘BioExcel-2. Centre of Excellence for Computational Biomolecular Research’ [823830]; MINECO Severo Ochoa Award of Excellence from the Government of Spain (awarded to IRB Barcelona); V.G. is a former EMBO long-term fellow; M.O. is an ICREA (Institucio Catalana ´de Recerca i Estudis Avancats) academia researcher.Peer reviewedOxford University PressEuropean Molecular Biology LaboratoryAgencia Estatal de Investigación (España)Generalitat de CatalunyaInstituto de Salud Carlos IIIInstituto Nacional de Bioinformática (España)European CommissionGenna, Vito [0000-0002-4664-8086]González, Carlos [0000-0001-8796-1282]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202420242023info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/343695https://api.elsevier.com/content/abstract/scopus_id/85162240719reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-096704-B-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-116620GB-I00info:eu-repo/grantAgreement/AEI//PID2021- 122478NB-100info:eu-repo/grantAgreement/EC/H2020/823830Nucleic acids researchhttps://doi.org/10.1093/nar/gkad309Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3436952026-05-22T06:33:51Z
dc.title.none.fl_str_mv Controlled sulfur-based engineering confers mouldability to phosphorothioate antisense oligonucleotides
title Controlled sulfur-based engineering confers mouldability to phosphorothioate antisense oligonucleotides
spellingShingle Controlled sulfur-based engineering confers mouldability to phosphorothioate antisense oligonucleotides
Genna, Vito
title_short Controlled sulfur-based engineering confers mouldability to phosphorothioate antisense oligonucleotides
title_full Controlled sulfur-based engineering confers mouldability to phosphorothioate antisense oligonucleotides
title_fullStr Controlled sulfur-based engineering confers mouldability to phosphorothioate antisense oligonucleotides
title_full_unstemmed Controlled sulfur-based engineering confers mouldability to phosphorothioate antisense oligonucleotides
title_sort Controlled sulfur-based engineering confers mouldability to phosphorothioate antisense oligonucleotides
dc.creator.none.fl_str_mv Genna, Vito
Iglesias-Fernández, Javier
Reyes-Fraile, Laura
Villegas, Nuria
Guckian, Kevin
Seth, Punit
Wan, Brad
Cabrero Fernández, Cristina
Terrazas, Montserrat
Brun-Heath, Isabelle
González, Carlos
Sciabola, Simone
Villalobos, Anabella
Orozco, Modesto
author Genna, Vito
author_facet Genna, Vito
Iglesias-Fernández, Javier
Reyes-Fraile, Laura
Villegas, Nuria
Guckian, Kevin
Seth, Punit
Wan, Brad
Cabrero Fernández, Cristina
Terrazas, Montserrat
Brun-Heath, Isabelle
González, Carlos
Sciabola, Simone
Villalobos, Anabella
Orozco, Modesto
author_role author
author2 Iglesias-Fernández, Javier
Reyes-Fraile, Laura
Villegas, Nuria
Guckian, Kevin
Seth, Punit
Wan, Brad
Cabrero Fernández, Cristina
Terrazas, Montserrat
Brun-Heath, Isabelle
González, Carlos
Sciabola, Simone
Villalobos, Anabella
Orozco, Modesto
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv European Molecular Biology Laboratory
Agencia Estatal de Investigación (España)
Generalitat de Catalunya
Instituto de Salud Carlos III
Instituto Nacional de Bioinformática (España)
European Commission
Genna, Vito [0000-0002-4664-8086]
González, Carlos [0000-0001-8796-1282]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description 13 pags., 6 figs., 2 tabs.
publishDate 2023
dc.date.none.fl_str_mv 2023
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/343695
https://api.elsevier.com/content/abstract/scopus_id/85162240719
url http://hdl.handle.net/10261/343695
https://api.elsevier.com/content/abstract/scopus_id/85162240719
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-096704-B-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-116620GB-I00
info:eu-repo/grantAgreement/AEI//PID2021- 122478NB-100
info:eu-repo/grantAgreement/EC/H2020/823830
Nucleic acids research
https://doi.org/10.1093/nar/gkad309
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
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