Nucleic Acids Research, Vol 25, Issue 10 1991-1998, Copyright © 1997 by Oxford University Press
J Lacoste, JC Francois and C Helene
Purine-rich (GA)- and (GT)-containing oligophosphorothioates were
investigated for their triplex-forming potential on a 23 bp DNA duplex
target. In our system, GA-containing oligophosphorothioates (23mer GA- PS)
were capable of triplex formation with binding affinities lower than
(GA)-containing oligophosphodiesters (23mer GA-PO). The orientation of the
third strand 23mers GA-PS and GA-PO was antiparallel to the purine strand
of the duplex DNA target. In contrast, (GT)- containing
oligophosphorothioates (23mer GT-PS) did not support triplex formation in
either orientation, whereas the 23mer GT-PO oligophosphodiester
demonstrated triplex formation in the antiparallel orientation. GA-PS
oligonucleotides, in contrast to GT-PS oligonucleotides, were capable of
self-association, but these self- associated structures exhibited lower
stabilities than those formed with GA-PO oligonucleotides, suggesting that
homoduplex formation (previously described for the 23mer GA-PO sequence by
Noonberg et al.) could not fully account for the decrease in triplex
stability when phosphorothioate linkages were used. The 23mer GA-PS
oligonucleotide was covalently linked via its 5'-end to an acridine
derivative (23mer Acr-GA-PS). In the presence of potassium cations, this
conjugate demonstrated triplex formation with higher binding affinity than
the unmodified 23mer GA-PS oligonucleotide and even than the 23mer GA-PO
oligonucleotide. A (GA)-containing oligophosphodiester with two
phosphorothioate linkages at both the 5'- and 3'-ends exhibited similar
binding affinity to duplex DNA compared with the unmodified GA-PO
oligophosphodiester. This capped oligonucleotide was more resistant to
nucleases than the GA-PO oligomer and thus represents a good alternative
for ex vivo applications of (GA)-containing, triplex- forming
oligonucleotides, allowing a higher binding affinity for its duplex target
without rapid cellular degradation.
ARTICLES
Triple helix formation with purine-rich phosphorothioate-containing oligonucleotides covalently linked to an acridine derivative
Laboratoire de Biophysique, Museum National d'Histoire Naturelle, INSERM Unite 201-CNRS UA 481, 43 rue Cuvier, 75231 Paris Cedex 05, France.
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