351. Novel oligonucleotides containing two 3'-ends complementary to target mRNA show optimal gene-silencing activity
- Author
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Nicola La Monica, Zhenhua Sun, Sudhir Agrawal, Weiwen Jiang, Dong Yu, Daqing Wang, Lakshmi Bhagat, Jimmy X. Tang, Mallikarjuna Putta, Tao Lan, Ekambar R. Kandimalla, and Hao Wang
- Subjects
Oligonucleotides ,Cell Line ,chemistry.chemical_compound ,Mice ,Drug Discovery ,Gene silencing ,Oligoribonucleotides ,Animals ,Humans ,Gene Silencing ,RNA, Messenger ,DNA Primers ,Messenger RNA ,Phosphorothioate Oligonucleotides ,biology ,Base Sequence ,Chemistry ,Oligonucleotide ,Ribozyme ,RNA ,Molecular biology ,Biochemistry ,Myeloid Differentiation Factor 88 ,biology.protein ,Molecular Medicine ,DNA - Abstract
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.
- Published
- 2011