Controlled sulfur-based engineering confers mouldability to phosphorothioate antisense oligonucleotides

TitleControlled sulfur-based engineering confers mouldability to phosphorothioate antisense oligonucleotides
Publication TypeJournal Article
Year of Publication2023
AuthorsGenna, Vito, Iglesias-Fernández Javier, Reyes-Fraile Laura, Villegas Núria, Guckian Kevin, Seth Punit, Wan Brad, Cabrero Cristina, Terrazas Montserrat, Brun-Heath Isabelle, González Carlos, Sciabola Simone, Villalobos Anabella, and Orozco Modesto
JournalNucleic Acids Research
Volume51
Issue10
Pagination4713 - 4725
Date Published06/2023
ISBN Number0305-1048
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.

URLhttps://doi.org/10.1093/nar/gkad309
Short TitleNucleic Acids Research
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