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Synthesis, gene silencing, and molecular modeling studies of 4'-C-aminomethyl-2'-O-methyl modified small interfering RNAs.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.ORCID iD: 0000-0002-7256-0758
2012 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 77, no 7, p. 3233-3245Article in journal (Refereed) Published
Abstract [en]

The linear syntheses of 4'-C-aminomethyl-2'-O-methyl uridine and cytidine nucleoside phosphoramidites were achieved using glucose as the starting material. The modified RNA building blocks were incorporated into small interfering RNAs (siRNAs) by employing solid phase RNA synthesis. Thermal melting studies showed that the modified siRNA duplexes exhibited slightly lower T(m) (∼1 °C/modification) compared to the unmodified duplex. Molecular dynamics simulations revealed that the 4'-C-aminomethyl-2'-O-methyl modified nucleotides adopt South-type conformation in a siRNA duplex, thereby altering the stacking and hydrogen-bonding interactions. These modified siRNAs were also evaluated for their gene silencing efficiency in HeLa cells using a luciferase-based reporter assay. The results indicate that the modifications are well tolerated in various positions of the passenger strand and at the 3' end of the guide strand but are less tolerated in the seed region of the guide strand. The modified siRNAs exhibited prolonged stability in human serum compared to unmodified siRNA. This work has implications for the use of 4'-C-aminomethyl-2'-O-methyl modified nucleotides to overcome some of the challenges associated with the therapeutic utilities of siRNAs.

Place, publisher, year, edition, pages
2012. Vol. 77, no 7, p. 3233-3245
National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-364935DOI: 10.1021/jo202666mPubMedID: 22372696OAI: oai:DiVA.org:uu-364935DiVA, id: diva2:1261193
Available from: 2018-11-06 Created: 2018-11-06 Last updated: 2019-03-29Bibliographically approved

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Nawale, Ganesh N.

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