uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Fine Tuning of Electrostatics Around the Internucleotidic Phosphate through Incorporations of Functionalized 2', 4'-Carbocyclic-LNAs and –ENAs Lead to Significant Modulation of Antisense Properties
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
Show others and affiliations
2009 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 74, no 1, 118-134 p.Article in journal (Refereed) Published
Abstract [en]

In the antisense (AS) and RNA interference (RNAi) technologies, the native single-stranded 2'-deoxyoligonucleotides (for AS) or double-stranded RNA (for RNAi) are chemically modified to bind to the target RNA in order to give improved downregulation of gene expression   through inhibition of RNA translation. It is shown here how the fine adjustment of the electrostatic interaction by alteration of the substituents as well as their stereochemical environment around the intemucleotidic phosphodiester moiety near the edge of the minor grove of the antisense oligonucleotides (AON)-RNA heteroduplex can lead to the modulation of the antisense properties. This was demonstrated through the synthesis of various modified carbocyclic-locked nucleic acids (LNAs) and -ethylene-bridged nucleic acids (ENAs) with hydroxyl and/or methyl substituents attached at the carbocyclic pan and their   integration into AONs by solid-phase DNA synthesis. The target affinity toward the complementary RNA and DNA, nuclease resistance, and RNase H elicitation by these modified AONs showed that both the nature of the modification (-OH versus -CH3) and their respective stereochemical orientations vis-a-vis vicinal phosphate play a very important role in modulating the AON properties. Whereas the affinity to the target RNA and the enzymatic stability of AONs were not favored by the hydrophobic and sterically bulky modifications in the center of the minor groove, their positioning at the edge of the minor groove near the phosphate linkage resulted in significantly improved nuclease resisitance without of target affinity. On the other hand, hydrophilic modification, such as a hydroxyl group, close to the phosphate linkage made the internucleotidic phosphodiester especially nucleolytically unstable, and hence was not recommended. The substitutions on the carbocyclic moiety of the carba-LNA and -ENA did not affect significantly the choice of the cleavage sites of RNase H mediated RNA cleavage in the AON/RNA hybrid duplex, but the cleavage rate depended on the modification site in the AON sequence. If the original preferred cleavage site by RNase H was included in the 4-5nt stretch from the 3'-end of the modification site in the AON, decreassed cleavage rate was observed. Upon screening of 52 modified AONs, containing 13 differently modified derivatives at C6' and C7' (or CS') of the carba-LNAs and -ENAs, two excellent modifications in the carba-LNA series were identified, which synergistically gave outstanding antisense properties such as the target RNA affinity, nuclease resistance, and RNase H activity and were deemed to be ideal candidates as potential antisense or siRNA therapeutic agents.

Place, publisher, year, edition, pages
2009. Vol. 74, no 1, 118-134 p.
National Category
Biological Sciences Natural Sciences
Identifiers
URN: urn:nbn:se:uu:diva-106719DOI: 10.1021/jo8016742ISI: 000262004000015OAI: oai:DiVA.org:uu-106719DiVA: diva2:225939
Available from: 2009-06-29 Created: 2009-06-29 Last updated: 2017-12-13
In thesis
1. Conformationally Constrained Nucleic Acids as Potential RNA Targeting Therapeutics
Open this publication in new window or tab >>Conformationally Constrained Nucleic Acids as Potential RNA Targeting Therapeutics
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Publisher
67 p.
National Category
Organic Chemistry
Research subject
Chemistry with specialization in Bioorganic Chemistry
Identifiers
urn:nbn:se:uu:diva-113680 (URN)
Public defence
2010-03-31, C10:301, BMC, Husargatan 3, Uppsala, 14:00 (English)
Opponent
Supervisors
Available from: 2010-03-10 Created: 2010-02-02 Last updated: 2010-03-11

Open Access in DiVA

No full text

Other links

Publisher's full text

Authority records BETA

Plashkevych, Oleksandr

Search in DiVA

By author/editor
Plashkevych, Oleksandr
By organisation
Bioorganic Chemistry
In the same journal
Journal of Organic Chemistry
Biological SciencesNatural Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 443 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf