AI Article Synopsis
- - A series of siRNA duplexes featuring cationic non-bridging 3',5'-linked phosphoramidate (PN) linkages were created to analyze their thermal stability and effectiveness in regulating firefly luciferase expression.
- - The findings indicate that PN modifications do not significantly destabilize the siRNA duplex, and the stability can be improved with specific RNA-like modifications.
- - Overall, the study suggests that these PN modifications could enhance the development of therapeutic siRNAs with better biological performance without compromising their potency or structure.
Article Abstract
A series of siRNA duplexes containing cationic non-bridging 3',5'-linked phosphoramidate (PN) linkages was designed and synthesized using a combination of phosphoramidite and H-phosphonate chemistries. Modified oligonucleotides were assayed for their thermal stability, helical structure, and ability to modulate the expression of firefly luciferase. We demonstrate that PN modifications of siRNAs are, in general, minimally destabilizing with respect to duplex thermal stability; destabilization can be mitigated through the incorporation of 2'-modified RNA-like residues or PN conjugates containing ionizable pendant moieties. We also demonstrate that single cationic dimethylethylenediamine PN linkages have little effect on siRNA potency, whether located in the passenger or guide strand of the duplex. Highly modified siRNA passenger strands were further modified with up to four cationic PN linkages, with little effect on duplex potency or helical structure. We envision that PN modifications could be useful in the production of therapeutic siRNAs with optimal biological properties.
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| http://dx.doi.org/10.1089/nat.2017.0702 | DOI Listing |
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