| Autor: |
Datta D; Alnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA. mmanoharan@alnylam.com., Kumar P; Alnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA. mmanoharan@alnylam.com., Mandal S; Axolabs GmbH, Fritz-Hornschuch-Strasse 9, 95326 Kulmbach, Germany., Krampert M; Axolabs GmbH, Fritz-Hornschuch-Strasse 9, 95326 Kulmbach, Germany., Egli M; Department of Biochemistry, School of Medicine Nashville, Vanderbilt University, TN 37232, USA., Hrdlicka PJ; Department of Chemistry, University of Idaho, Moscow, ID-83844, USA., Manoharan M; Alnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA. mmanoharan@alnylam.com. |
| Abstrakt: |
Conformationally constrained nucleotides, LNA or α-L-LNA, at the 5' terminus of the antisense strand impeded gene silencing of small interfering RNA (siRNA) by hindering phosphorylation, thereby deterring loading into the RNA-induced silencing complex. Installation of a phosphate mimic, ( E )-vinyl phosphonate (VP), improved activity considerably. Gene silencing was more efficient when the antisense strand of the siRNA was modified with 5'-VP-α-L-LNA, which adopts a C3'- exo (south) conformation, than when the antisense strand was modified with 5'-VP-LNA, which adopts a C3'- endo (north) pucker. These data underscore the critical role of conformation of nucleotides in RNA interference. |
