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Molecular Structure of the Core-Modified siRNA Duplexes Containing Diastereomeric Pair of [C6′(R)-OH]- versus [C6′(S)-OH]-carba-LNAs Suggests a Model for RNAi Action
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
2011 (English)In: Nucleosides, Nucleotides & Nucleic Acids, ISSN 1525-7770, E-ISSN 1532-2335, Vol. 30, no 11, 815-825 p.Article in journal (Refereed) Published
Abstract [en]

Molecular structures of native and a pair of modified small interfering RNA-RNA duplexes containing carbocyclic [6'-(R)-OH/7'-(S)-methyl]- and [6'-(S)-OH/7'-(S)-methyl]-carba-LNA-thymine nucleotides, which are two diastereomeric analogs of the native T nucleotide, incorporated at position 13 in the antisense (AS) strand of siRNA, have been simulated using molecular mechanics/dynamics techniques. The main aim of the project has been to find a plausible structural explanation of why modification of siRNA at T(13) position by the [6'(R)-O-(p-Toluoyl)-7' (S)-methyl]-carba-LNA-Thymine [IC(50) of 3.32 +/- 0.17 nM] is ca 24 times more active as an RNA silencing agent against the target HIV-1 TAR RNA than the [6' (S)-O-(p-Toluoyl)-7' (S)-methyl]-counterpart [IC(50) of 79.8 +/- 17 nM] [1]. The simulations reveal that introduction of both C6' (R)-OH and C6' (S)-OH stereoisomers does not lead even to local perturbation of the siRNA-RNA duplex structures compared to the native, and the only significant difference between 6' (S)- and 6' (R)-diastereomers found is the exposure of the 6'-OH group of the 6' (R)-diastereoisomer toward the edge of the duplex while the 6'-hydroxyl group of the 6' (S)-diastereoisomer is somewhat buried in the minor groove of the duplex. This rules out a hypothesis about any possible local distortion by the nature of chemical modification of the siRNA-target the RNA duplex, which might have influenced the formation of the effective RNA silencing complex (RISC) and puts some weight on the hypothesis about the 6'-hydroxy group being directly involved with most probably Ago protein, since it is known from exhaustive X-ray studies [2, 3] that the core residues are indeed involved with hydrogen bonding with the internucleotidyl phosphates.

Place, publisher, year, edition, pages
2011. Vol. 30, no 11, 815-825 p.
Keyword [en]
siRNA, chemical modification, carba-LNA, molecular, structure, RNAi
National Category
Cell Biology
URN: urn:nbn:se:uu:diva-172201DOI: 10.1080/15257770.2011.586956ISI: 000298738200001OAI: oai:DiVA.org:uu-172201DiVA: diva2:513592
Available from: 2012-04-03 Created: 2012-04-02 Last updated: 2012-07-11Bibliographically approved

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Plashkevych, OleksandrChattopadhyaya, Jyoti
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