Controlled sulfur-based engineering confers mouldability to phosphorothioate antisense oligonucleotides
| العنوان: | Controlled sulfur-based engineering confers mouldability to phosphorothioate antisense oligonucleotides |
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| المؤلفون: | Vito Genna, Javier Iglesias-Fernández, Laura Reyes-Fraile, Nuria Villegas, Kevin Guckian, Punit Seth, Brad Wan, Cristina Cabrero, Montserrat Terrazas, Isabelle Brun-Heath, Carlos González, Simone Sciabola, Anabella Villalobos, Modesto Orozco |
| المصدر: | Nucleic Acids Research. |
| بيانات النشر: | Oxford University Press (OUP), 2023. |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | Genetics |
| الوصف: | 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. |
| تدمد: | 1362-4962 0305-1048 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::1e3004caa65074a2cf728a872c262642 https://doi.org/10.1093/nar/gkad309 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi...........1e3004caa65074a2cf728a872c262642 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 13624962 03051048 |
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