Controlled sulfur-based engineering confers mouldability to phosphorothioate antisense oligonucleotides

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 n...

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Detalles Bibliográficos
Autores: Genna, Vito, Iglesias Fernández, Javier, Reyes Fraile, Laura, Villegas, Núria, Guckian, Kevin, Seth, Punit, Wan, Brad, Cabrero, Carlos, Terrazas Martínez, Montserrat, Brun Heath, Isabelle, González, Carlos, Sciabola, Simone, Villalobos, Anabella, Orozco López, Modesto
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/199383
Acceso en línea:https://hdl.handle.net/2445/199383
Access Level:acceso abierto
Palabra clave:Oligonucleòtids
ADN
ARN
Oligonucleotides
DNA
RNA
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repository_id_str
spelling Controlled sulfur-based engineering confers mouldability to phosphorothioate antisense oligonucleotidesGenna, VitoIglesias Fernández, JavierReyes Fraile, LauraVillegas, NúriaGuckian, KevinSeth, PunitWan, BradCabrero, CarlosTerrazas Martínez, MontserratBrun Heath, IsabelleGonzález, CarlosSciabola, SimoneVillalobos, AnabellaOrozco López, ModestoOligonucleòtidsADNARNOligonucleotidesDNARNAPhosphorothioates (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.2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/199383Articles publicats en revistes (Bioquímica i Biomedicina Molecular)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1093/nar/gkad309Nucleic Acids Research, 2023, Vol.51, num. 10, p. 4713–4725https://doi.org/10.1093/nar/gkad309cc by (c) Genna, Vito et al., 2023http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1993832026-05-27T06:46:51Z
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
Oligonucleòtids
ADN
ARN
Oligonucleotides
DNA
RNA
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, Núria
Guckian, Kevin
Seth, Punit
Wan, Brad
Cabrero, Carlos
Terrazas Martínez, Montserrat
Brun Heath, Isabelle
González, Carlos
Sciabola, Simone
Villalobos, Anabella
Orozco López, Modesto
author Genna, Vito
author_facet Genna, Vito
Iglesias Fernández, Javier
Reyes Fraile, Laura
Villegas, Núria
Guckian, Kevin
Seth, Punit
Wan, Brad
Cabrero, Carlos
Terrazas Martínez, Montserrat
Brun Heath, Isabelle
González, Carlos
Sciabola, Simone
Villalobos, Anabella
Orozco López, Modesto
author_role author
author2 Iglesias Fernández, Javier
Reyes Fraile, Laura
Villegas, Núria
Guckian, Kevin
Seth, Punit
Wan, Brad
Cabrero, Carlos
Terrazas Martínez, Montserrat
Brun Heath, Isabelle
González, Carlos
Sciabola, Simone
Villalobos, Anabella
Orozco López, Modesto
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Oligonucleòtids
ADN
ARN
Oligonucleotides
DNA
RNA
topic Oligonucleòtids
ADN
ARN
Oligonucleotides
DNA
RNA
description 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.
publishDate 2023
dc.date.none.fl_str_mv 2023
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/2445/199383
url https://hdl.handle.net/2445/199383
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/10.1093/nar/gkad309
Nucleic Acids Research, 2023, Vol.51, num. 10, p. 4713–4725
https://doi.org/10.1093/nar/gkad309
dc.rights.none.fl_str_mv cc by (c) Genna, Vito et al., 2023
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Genna, Vito et al., 2023
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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