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J Med Chem. 2011 Apr 28;54(8):3027-36. doi: 10.1021/jm200113t. Epub 2011 Apr 5.

Novel oligonucleotides containing two 3'-ends complementary to target mRNA show optimal gene-silencing activity.

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Idera Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, United States.


Oligonucleotides are being employed for gene-silencing activity by a variety of mechanisms, including antisense, ribozyme, and siRNA. In the present studies, we designed novel oligonucleotides complementary to targeted mRNAs and studied the effect of 3'-end exposure and oligonucleotide length on gene-silencing activity. We synthesized both oligoribonucleotides (RNAs) and oligodeoxynucleotides (DNAs) with phosphorothioate backbones, consisting of two identical segments complementary to the targeted mRNA attached through their 5'-ends, thereby containing two accessible 3'-ends; these compounds are referred to as gene-silencing oligonucleotides (GSOs). RNA and/or DNA GSOs targeted to MyD88, VEGF, and TLR9 mRNAs had more potent gene-silencing activity than did antisense phosphorothioate oligonucleotides (PS-oligos) in cell-based assays and in vivo. Of the different lengths of GSOs evaluated, 19-mer long RNA and DNA GSOs had the best gene-silencing activity both in vitro and in vivo. These results suggest that GSOs are novel agents for gene silencing that can be delivered systemically with broader applicability.

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