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

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


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.

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line
  • DNA Primers
  • Gene Silencing*
  • Humans
  • Mice
  • Myeloid Differentiation Factor 88 / genetics
  • Oligonucleotides / chemistry
  • Oligonucleotides / pharmacology*
  • RNA, Messenger / chemistry*


  • DNA Primers
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Oligonucleotides
  • RNA, Messenger