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Effect of North Bicyclo[3.1.0]hexane 2 '-Deoxy-pseudosugars on RNA Interference: A Novel Class of siRNA Modification

  1. Author:
    Terrazas, M.
    Ocampo, S. M.
    Perales, J. C.
    Marquez, V. E.
    Eritja, R.

  2. Author Address

    [Terrazas, M; Ocampo, SM; Eritja, R] Spanish Res Council CSIC, Inst Adv Chem Catalonia IQAC, Inst Res Biomed IRB Barcelona, CIBER BBN, Barcelona 08028, Spain [Perales, JC] Univ Barcelona, Sch Med, Dept Ciencies Fisiol, Barcelona 08907, Spain [Marquez, VE] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA;Eritja, R (reprint author), Spanish Res Council CSIC, Inst Adv Chem Catalonia IQAC, Inst Res Biomed IRB Barcelona, CIBER BBN, Cluster Bldg,Baldiri & Reixac 10, Barcelona 08028, Spain;recgma@cid.csic.es
    1. Year: 2011
    2. Date: May
  2. Journal: Chembiochem
    1. 12
    2. 7
    3. Pages: 1056-1065
  4. Type of Article: Article
  5. ISSN: 1439-4227
  1. Abstract:

    North bicyclo methanocarba thymidine (T(N)) nucleosides were substituted into siRNAs to investigate the effect of bicyclo-[3.1.0]hexane 2'-deoxy-pseudosugars on RNA interference activity. Here we provide evidence that these modified siRNAs are compatible with the intracellular RNAi machinery. We studied the effect of the T(N) modification in a screen involving residue- specific changes in an siRNA targeting Renilla luciferase and we applied the most effective pattern of modification to the knockdown of murine tumor necrosis factor (TNF-alpha). We also showed that incorporation of T(N) units into siRNA duplexes increased their thermal stabilities, substantially enhanced serum stabilities, and decreased innate immunostimulation. Comparative RNAi studies involving the T(N) substitution and locked nucleic acids (LNAs) showed that the gene-silencing activities of T(N)-modified siRNAs were comparable to those obtained with the LNA modification. An advantage of the North 2'-deoxy-methanocarba modification is that it may be explored further in the future by changing the 2'-position. The results from these studies suggest that this modification might be valuable for the development of siRNAs for therapeutic applications.

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External Sources

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  2. DOI: 10.1002/cbic.201000791
  3. View record in Web of Science®
  4. WOS: 000289858200013

Library Notes

  1. Fiscal Year: FY2010-2011
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