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Rationally Targeted, Conformationally Constrained, Oxetane-Modified Oligonucleotides Demonstrate Efficient Gene-Silencing Activity in a Cellular System
aDepartment of Hematology, Pomeranian Medical University, Szczecin, Poland bDivison of Hematology/Oncology, Department of Medicine, and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Address for correspondence: J. B. Opalinska, Department of Hematology, Pomeranian Medical University, Konopnickiej 76/3, Unii Lubelskiej 1, Szczecin, Poland. Voice: 0048-91-4253349; fax: 0048-91-4253357. jopal{at}poczta.onet.pl
Antisense oligodeoxynucleotides (AS ODN) have been employed as gene-silencing agents in the laboratory and, in the clinic. The in vivo use of these molecules has been facilitated by chemical modifications to the DNA backbone which augment their nuclease stability. Attempts to further improve the efficacy of AS ODN have largely focused on 2' alterations of the ribose sugar that make the molecules more RNA like in structure. This increases the Tm of formed DNA/RNA hybrids but simultaneously prevents binding of RNaseH which is important for ODN effectiveness. Herein, we demonstrate the use of AS ODN containing nucleosides with a novel oxetane (OXE) modification [oxetane, 1-(1', 3'-O-anhydro-ß-D-psicofuranosyl nucleosides)] which augments Tm, enhances nuclease stability, and is permissive of RNaseH activation. We also illustrate herein the value of rational targeting of OXE modified, and by analogy, AS ODN of any chemical modification.
Key Words: antisense oligodeoxynucleotides • oxetane • c-myb • gene silencing • rational targeting This article has been cited by other articles:
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