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Nucleic Acids Research 2006 34(8):2247-2257; doi:10.1093/nar/gkl249
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Published online 2 May 2006

© The Author 2006. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Article

Hydroxyproline-based DNA mimics provide an efficient gene silencing in vitro and in vivo

Vladimir A. Efimov*, Klara R. Birikh, Dmitri B. Staroverov1, Sergei A. Lukyanov, Maria B. Tereshina, Andrey G. Zaraisky and Oksana G. Chakhmakhcheva

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS Moscow 117997, Russia 1 Evrogen, ul.Miklukho-Maklaya 16/10 Moscow 117997, Russia

*To whom correspondence should be addressed. Tel: +7 495 3365911; Fax: +7 495 3306738; Email: eva{at}mail.ibch.ru

Received March 2, 2006. Revised March 20, 2006. Accepted March 30, 2006.

To be effective, antisense molecules should be stable in biological fluids, non-toxic, form stable and specific duplexes with target RNAs and readily penetrate through cell membranes without non-specific effects on cell function. We report herein that negatively charged DNA mimics representing chiral analogues of peptide nucleic acids with a constrained trans-4-hydroxy-N-acetylpyrrolidine-2-phosphonate backbone (pHypNAs) meet these criteria. To demonstrate this, we compared silencing potency of these compounds with that of previously evaluated as efficient gene knockdown molecules hetero-oligomers consisting of alternating phosphono-PNA monomers and PNA-like monomers based on trans-4-hydroxy-L-proline (HypNA-pPNAs). Antisense potential of pHypNA mimics was confirmed in a cell-free translation assay with firefly luciferase as well as in a living cell assay with green fluorescent protein. In both cases, the pHypNA antisense oligomers provided a specific knockdown of a target protein production. Confocal microscopy showed that pHypNAs, when transfected into living cells, demonstrated efficient cellular uptake with distribution in the cytosol and nucleus. Also, the high potency of pHypNAs for down-regulation of Ras-like GTPase Ras-dva in Xenopus embryos was demonstrated in comparison with phosphorodiamidate morpholino oligomers. Therefore, our data suggest that pHypNAs are novel antisense agents with potential widespread in vitro and in vivo applications in basic research involving live cells and intact organisms.


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