Nucleic Acids Research, Vol 25, Issue 2 370-378, Copyright © 1997 by Oxford University Press
ER Kandimalla, A Manning, Q Zhao, DR Shaw, RA Byrn, V Sasisekharan and S Agrawal
We have designed and synthesized mixed backbone oligonucleotides (MBOs)
containing 2'-5'-ribo- and 3'-5'-deoxyribonucleotide segments. Thermal
melting studies of the phosphodiester MBOs (three 2'-5'linkages at each
end) with the complementary 3'-5'-DNA and -RNA target strands suggest that
2'-5'-ribonucleoside incorporation into 3'-5'- oligodeoxyribonucleotides
reduces binding to the target strands compared with an all
3'-5'-oligodeoxyribonucleotide of the same sequence and length. Increasing
the number of 2'-5'linkages (from six to nine) further reduces binding to
the DNA target strand more than the RNA target strand [Kandimalla,E.R. and
Agrawal,S. (1996)Nucleic Acids Symp. Ser., 35, 125-126]. Phosphorothioate
(PS) analogs of MBOs destabilize the duplex with the DNA target strand more
than the duplex with the RNA target strand. Circular dichroism studies
indicate that the duplexes of MBOs with the DNA and RNA target strands have
spectral characteristics of both A- and B-type conformations. Compared with
the control oligonucleotide, MBOs exhibit moderately higher stability
against snake venom phosphodiesterase, S1 nuclease and in fetal calf serum.
Although 2'-5'modification does not evoke RNase H activity, this
modification does not effect the RNase H activation property of the 3'-
5'-deoxyribonucleotide segment adjacent to the modification. In vitro
studies with MBOs suggest that they have lesser effects on cell
proliferation, clotting prolongation and hemolytic complement lysis than do
control PS oligodeoxyribonucleotides. PS analogs of MBOs show HIV-1
inhibition comparable with that of a control PS oligodeoxyribonucleotide
with all 3'-5'linkages. The current results suggest that a limited number
of 2'-5'linkages could be used in conjunction with PS oligonucleotides to
further modulate the properties of antisense oligonucleotides as
therapeutic agents.
ARTICLES
Mixed backbone antisense oligonucleotides: design, biochemical and biological properties of oligonucleotides containing 2'-5'-ribo- and 3'- 5'-deoxyribonucleotide segments
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