Biological effects of hexitol and altritol-modified siRNAs targeting B-Raf.
Increasing the effectiveness of siRNAs through chemical modification is an important task. Here we describe altritol and hexitol modified oligonucleotides targeting the B-Raf oncogene that is critical for the growth and survival of melanoma cells. Using assays for apoptosis, DNA synthesis, colony formation and B-Raf protein and message levels, we demonstrate that certain hexitol modifications can improve the effectiveness of B-Raf siRNAs and also increase duration of action. Altritol modified siRNAs were similar to or slightly less effective than unmodified B-Raf siRNA. Modifications at the 3' or 5' end of the sense strand, at the 3' end of the antisense strand, or within either strand were well tolerated. The basis for the increased effectiveness of the hexitol-modified siRNAs is not fully understood but may be partly due to increased stability to nucleases.
Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
Michael
M
Fisher
Mikhail
M
Abramov
Arthur
A
Van Aerschot
Jef
J
Rozenski
Vidula
V
Dixit
Rudy L
RL
Juliano
Piet
P
Herdewijn
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism*; D013402:Sugar Alcohols / Q000378:metabolism*
D034741:RNA, Small Interfering; D013402:Sugar Alcohols; C543192:hexitol; C042890:altritol; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf