Nucleic Acids Research, Vol 24, Issue 8 1508-1514, Copyright © 1996 by Oxford University Press
S Gryaznov, T Skorski, C Cucco, M Nieborowska-Skorska, CY Chiu, D Lloyd, JK Chen, M Koziolkiewicz and B Calabretta
Uniformly modified oligonucleotide N3'-->P5' phosphoramidates, where
every 3'-oxygen is replaced by a 3'-amino group, were synthesized. These
compounds have very high affinity to single-stranded RNAs and thus have
potential utility as antisense agents. As was shown in this study, the
oligonucleotide phosphoramidates are resistant to digestion with snake
venom phosphodiesterase, to nuclease activity in a HeLa cell nuclear
extract, or to nuclease activity in 50% human plasma, where no significant
hydrolysis was observed after 8 h. These compounds were used in various in
vitro cellular systems as antisense compounds addressed to different
targeted regions of c-myb, c-myc and bcr-abl mRNAs. C-myb antisense
phosphoramidates at 5 microM caused sequence and dose-dependent inhibition
of HL-60 cell proliferation and a 75% reduction in c-myb protein and RNA
levels, as determined by Western blot and RT-PCR analysis. Analogous
results were observed for anti-c- myc phosphoramidates, where a complete
cytostatic effect for HL-60 cells was observed at 1 microM concentration
for fully complementary, but not for mismatched compounds, which were
indistinguishable from untreated controls. This was correlated with a 93%
reduction in c-myc protein level. Moreover, colony formation by the primary
CML cells was also inhibited 75-95% and up to 99% by anti-c-myc and
anti-bcr-abl phosphoramidate oligonucleotides, respectively, in a sequence-
and dose- dependent manner within a 0.5 nM-5 microM dose range. At these
concentrations the colony-forming ability of normal bone marrow cells was
not affected. The presented in vitro data indicate that oligonucleotide
N3'-->P5' phosphoramidates could be used as specific and efficient
antisense agents.
ARTICLES
Oligonucleotide N3'-->P5' phosphoramidates as antisense agents
Lynx Therapeutics, Inc., Hayward, CA 94545, USA.
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