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J Biol Chem, Vol. 274, Issue 3, 1715-1722, January 15, 1999
From the Departments of The use of antisense oligonucleotides to inhibit
the expression of targeted mRNA sequences is becoming increasingly
commonplace. Although effective, the most widely used oligonucleotide
modification (phosphorothioate) has some limitations. In previous
studies we have described a 20-mer phosphorothioate
oligodeoxynucleotide inhibitor of human protein kinase C-
Characterization of a Potent and Specific Class of Antisense
Oligonucleotide Inhibitor of Human Protein Kinase C-
Expression
,,
Pharmacology,
Molecular Pharmacology, § Analytical/Physical
Chemistry, and ¶ Medicinal Chemistry, ISIS Pharmaceuticals,
Carlsbad, California 92008
expression. In an effort to identify improved antisense inhibitors of
protein kinase C expression, a series of 2' modifications have been
incorporated into the protein kinase C- targeting oligonucleotide,
and the effects on oligonucleotide biophysical characteristics and
pharmacology evaluated. The incorporation of 2'-O-(2-methoxy)ethyl
chemistry resulted in a number of significant improvements in
oligonucleotide characteristics. These include an increase in
hybridization affinity toward a complementary RNA (1.5° C per
modification) and an increase in resistance toward both 3'-exonuclease
and intracellular nucleases. These improvements result in a substantial
increase in oligonucleotide potency (>20-fold after 72 h). The
most active compound identified was used to examine the role played by
protein kinase C- in mediating the phorbol ester-induced changes in
c-fos, c-jun, and junB
expression in A549 lung epithelial cells. Depletion of protein kinase
C- protein expression by this oligonucleotide lead to a reduction in
c-jun expression but not c-fos or
junB. These results demonstrate that
2'-O-(2-methoxy)ethyl-modified antisense oligonucleotides are 1)
effective inhibitors of protein kinase C- expression, and 2)
represent a class of antisense oligonucleotide which are much more
effective inhibitors of gene expression than the widely used
phosphorothioate antisense oligodeoxynucleotides.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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