Fully 2'-modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA.
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.
Allerson
Charles R
CR
Department of Medicinal Chemistry, Isis Pharmaceuticals, 2292 Faraday Avenue, Carlsbad, California 92008, USA. callerson@isisph.com
Sioufi
Namir
N
Jarres
Russell
R
Prakash
Thazha P
TP
Naik
Nishant
N
Berdeja
Andres
A
Wanders
Lisa
L
Griffey
Richard H
RH
Swayze
Eric E
EE
Bhat
Balkrishen
B
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*
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