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Title: Inhibition of MDR1 expression with altritol modified siRNAs
Authors: Fisher, Michael
Abramov, Mikhail
Van Aerschot, Arthur
Xu, Dong
Juliano, Rudolph L
Herdewijn, Piet # ×
Issue Date: Feb-2007
Publisher: Oxford univ press
Series Title: Nucleic acids research vol:35 issue:4 pages:1064-1074
Abstract: Altritol-modified nucleic acids (ANAs) support RNA-like A-form structures when included in oligonucleotide duplexes. Thus altritol residues seem suitable as candidates for the chemical modification of siRNAs. Here we report that ANA-modified siRNAs targeting the MDR1 gene can exhibit improved efficacy as compared to unmodified controls. This was particularly true of ANA modifications at or near the 3' end of the sense or antisense strands, while modification at the 5' end of the antisense strand resulted in complete loss of activity. Multiple ANA modifications within the sense strand were also well tolerated. Duplexes with ANA modifications at appropriate positions in both strands were generally more effective than duplexes with one modified and one unmodified strand. Initial evidence suggests that the loss of activity associated with ANA modification of the 5'-antisense strand may be due to reduced phosphorylation at this site by cellular kinases. Treatment of drug resistant cells with MDR1-targeted siRNAs resulted in reduction of P-glycoprotein (Pgp) expression, parallel reduction in MDR1 message levels, increased accumulation of the Pgp substrate rhodamine 123, and reduced resistance to anti-tumor drugs. Interestingly, the duration of action of some of the ANA-modified siRNAs was substantially greater than that of unmodified controls. These observations suggest that altritol modifications may be helpful in developing siRNAs with enhanced pharmacological effectiveness.
URI: 
ISSN: 0305-1048
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Medicinal Chemistry
× corresponding author
# (joint) last author

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