Fully 2'-modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA

J Med Chem. 2005 Feb 24;48(4):901-4. doi: 10.1021/jm049167j.

Abstract

We have identified a small interfering RNA (siRNA) motif, consisting entirely of 2'-O-methyl and 2'-fluoro nucleotides, that displays enhanced plasma stability and increased in vitro potency. At one site, this motif showed remarkable >500-fold improvement in potency over the unmodified siRNA. This marks the first report of such a potent fully modified motif, which may represent a useful design for therapeutic oligonucleotides.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Drug Carriers
  • Drug Stability
  • HeLa Cells
  • Humans
  • Mice
  • Oligonucleotides / chemical synthesis*
  • Oligonucleotides / chemistry
  • Oligonucleotides / pharmacology
  • PTEN Phosphohydrolase
  • Phosphatidylethanolamines
  • Phosphoric Monoester Hydrolases / biosynthesis
  • Phosphoric Monoester Hydrolases / genetics*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / chemistry*
  • RNA, Small Interfering / chemistry*
  • RNA, Small Interfering / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Structure-Activity Relationship
  • Transfection
  • Tumor Suppressor Proteins / biosynthesis
  • Tumor Suppressor Proteins / genetics*

Substances

  • Drug Carriers
  • Oligonucleotides
  • Phosphatidylethanolamines
  • RNA, Messenger
  • RNA, Small Interfering
  • Tumor Suppressor Proteins
  • 1,2-dielaidoylphosphatidylethanolamine
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human