Skip Navigation

Nucleic Acids Research 2004 32(19):5791-5799; doi:10.1093/nar/gkh893
This Article
Right arrow Full Text Freely available
Right arrow Print PDF (450K) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (19)
Right arrowRequest Permissions
Right arrow Commercial Re-use Guidelines
for Open Access NAR Content
Google Scholar
Right arrow Articles by Opalinska, J. B.
Right arrow Articles by Gewirtz, A. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Opalinska, J. B.
Right arrow Articles by Gewirtz, A. M.
Related Collections
Right arrow Nucleic acid modification
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published online 28 October 2004

Nucleic Acids Research, Vol. 32 No. 19 © Oxford University Press 2004; all rights reserved

Oxetane modified, conformationally constrained, antisense oligodeoxyribonucleotides function efficiently as gene silencing molecules

J. B. Opalinska1,2, A. Kalota1, Lida K. Gifford3, Ponzy Lu3, Kuang-Yu Jen1, P. I. Pradeepkumar4, J. Barman4, T. K. Kim1, C. R. Swider1, J. Chattopadhyaya4 and A. M. Gewirtz1,*

1 Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA, 2 Department of Hematology, Pomeranian Medical University, Szczecin, Poland, 3 Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA and 4 Department of Bioorganic Chemistry, University of Uppsala, Uppsala, Sweden

* To whom correspondence should be addressed at Rm 713, BRB II/III, University of Pennsylvania School of Medicine, 421 Curie Blvd., Philadelphia, PA 19104, USA. Tel: +1 215 898 4499; Fax: +1 215 573 2078; Email: gewirtz{at}mail.med.upenn.edu

Received as resubmission September 2, 2004; Revised September 20, 2004; Accepted September 28, 2004

Incorporation of nucleosides with novel base-constraining oxetane (OXE) modifications [oxetane, 1-(1',3'-O-anhydro-ß-D-psicofuranosyl nucleosides)] into antisense (AS) oligodeoxyribonucleotides (ODNs) should greatly improve the gene silencing efficiency of these molecules. This is because OXE modified bases provide nuclease protection to the natural backbone ODNs, can impart Tm values similar to those predicted for RNA–RNA hybrids, and not only permit but also accelerate RNase H mediated catalytic activity. We tested this assumption in living cells by directly comparing the ability of OXE and phosphorothioate (PS) ODNs to target c-myb gene expression. The ODNs were targeted to two different sites within the c-myb mRNA. One site was chosen arbitrarily. The other was a ‘rational’ choice based on predicted hybridization accessibility after physical mapping with self-quenching reporter molecules (SQRM). The Myb mRNA and protein levels were equally diminished by OXE and PS ODNs, but the latter were delivered to cells with approximately six times greater efficiency, suggesting that OXE modified ODNs were more potent on a molar basis. The rationally targeted molecules demonstrated greater silencing efficiency than those directed to an arbitrarily chosen mRNA sequence. We conclude that rationally targeted, OXE modified ODNs, can function efficiently as gene silencing agents, and hypothesize that they will prove useful for therapeutic purposes.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Nucleic Acids ResHome page
X. Tang, J. Swaminathan, A. M. Gewirtz, and I. J. Dmochowski
Regulating gene expression in human leukemia cells using light-activated oligodeoxynucleotides
Nucleic Acids Res., February 2, 2008; 36(2): 559 - 569.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
Y. Drabsch, H. Hugo, R. Zhang, D. H. Dowhan, Y. R. Miao, A. M. Gewirtz, S. C. Barry, R. G. Ramsay, and T. J. Gonda
Mechanism of and requirement for estrogen-regulated MYB expression in estrogen-receptor-positive breast cancer cells
PNAS, August 21, 2007; 104(34): 13762 - 13767.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
M. Maderia, S. Shenoy, Q. N. Van, V. E. Marquez, and J. J. Barchi Jr
Biophysical studies of DNA modified with conformationally constrained nucleotides: comparison of 2'-exo (north) and 3'-exo (south) 'locked' templates
Nucleic Acids Res., March 19, 2007; 35(6): 1978 - 1991.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
T. Dowler, D. Bergeron, A.-L. Tedeschi, L. Paquet, N. Ferrari, and M. J. Damha
Improvements in siRNA properties mediated by 2'-deoxy-2'-fluoro-{beta}-D-arabinonucleic acid (FANA)
Nucleic Acids Res., March 22, 2006; 34(6): 1669 - 1675.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
A. Kalota, L. Karabon, C. R. Swider, E. Viazovkina, M. Elzagheid, M. J. Damha, and A. M. Gewirtz
2'-Deoxy-2'-fluoro-{beta}-D-arabinonucleic acid (2'F-ANA) modified oligonucleotides (ON) effect highly efficient, and persistent, gene silencing
Nucleic Acids Res., January 18, 2006; 34(2): 451 - 461.
[Abstract] [Full Text] [PDF]

Home page
 ASH ANNUAL MEETING ABSTRACTSHome page
A. Kalota, L. Karabon, C. S. Swider, E. Viazovkina, M. Elzagheid, M. J. Damha, and A. M. Gewirtz
A Novel 2'-Deoxy-2'-Fluoro (2'F-ANA) Ribose Modification Significantly Enhances the Duration, and Efficiency, of Nucleic Acid Mediated Gene Silencing.
Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 3062 - 3062.
[Abstract]

Home page
 Clin. Cancer Res.Home page
J. B. Opalinska, B. Machalinski, J. Ratajczak, M. Z. Ratajczak, and A. M. Gewirtz
Multigene Targeting with Antisense Oligodeoxynucleotides: An Exploratory Study Using Primary Human Leukemia Cells
Clin. Cancer Res., July 1, 2005; 11(13): 4948 - 4954.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.