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http://hdl.handle.net/2445/199383
Title: | Controlled sulfur-based engineering confers mouldability to phosphorothioate antisense oligonucleotides |
Author: | Genna, Vito Iglesias Fernández, Javier Reyes Fraile, Laura Villegas, Nuria Guckian, Kevin Seth, Punit Wan, Brad Cabrero, Carlos Terrazas Martínez, Montserrat Brun Heath, Isabelle González, Carlos Sciabola, Simone Villalobos, Anabella Orozco López, Modesto |
Keywords: | Oligonucleòtids ADN ARN Oligonucleotides DNA RNA |
Issue Date: | 9-Jun-2023 |
Abstract: | 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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1093/nar/gkad309 |
It is part of: | Nucleic Acids Research, 2023, Vol.51, num. 10, p. 4713–4725 |
URI: | http://hdl.handle.net/2445/199383 |
Related resource: | https://doi.org/10.1093/nar/gkad309 |
ISSN: | 1362-4962 |
Appears in Collections: | Articles publicats en revistes (Química Inorgànica i Orgànica) Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona)) Articles publicats en revistes (Bioquímica i Biomedicina Molecular) Articles publicats en revistes (Institut de Biomedicina (IBUB)) |
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NAR_Genna et al_2023.pdf | 3.31 MB | Adobe PDF | View/Open |
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