title: Fully 2'-modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA.
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.
authors.affiliation: Department of Medicinal Chemistry, Isis Pharmaceuticals, 2292 Faraday Avenue, Carlsbad, California 92008, USA. callerson@isisph.com
authors.forename: Charles R
authors.initials: CR
authors.lastname: Allerson
authors.forename: Namir
authors.initials: N
authors.lastname: Sioufi
authors.forename: Russell
authors.initials: R
authors.lastname: Jarres
authors.forename: Thazha P
authors.initials: TP
authors.lastname: Prakash
authors.forename: Nishant
authors.initials: N
authors.lastname: Naik
authors.forename: Andres
authors.initials: A
authors.lastname: Berdeja
authors.forename: Lisa
authors.initials: L
authors.lastname: Wanders
authors.forename: Richard H
authors.initials: RH
authors.lastname: Griffey
authors.forename: Eric E
authors.initials: EE
authors.lastname: Swayze
authors.forename: Balkrishen
authors.initials: B
authors.lastname: Bhat
mesh_terms: D000818:Animals; D004337:Drug Carriers; D004355:Drug Stability; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009841:Oligonucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051059:PTEN Phosphohydrolase; D010714:Phosphatidylethanolamines; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D004337:Drug Carriers; D009841:Oligonucleotides; D010714:Phosphatidylethanolamines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; C020888:1,2-dielaidoylphosphatidylethanolamine; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human