INHIBITION OF DENGUE VIRUS BY NOVEL, MODIFIED ANTISENSE OLIGONUCLEOTIDES

Five different target regions along the length of the dengue virus typ e 2 genome were compared for inhibition of the virus following intrace llular injection of the cognate antisense oligonucleotides and their a nalogs. Unmodified phosphodiester oligonucleotides as well as the corr esponding phosphorothioate oligonucleotides were ineffective in bringi ng about a significant inhibition of the virus. Novel modified phospho rothioate oligonucleotides in which the C-5 atoms of uridines and cyti dines were replaced by propynyl groups caused a significant inhibition of the virus. Antisense oligonucleotide directed against the target r egion near the translation initiation site of dengue virus RNA was the most effective, followed dy antisense oligonucleotide directed agains t a target in the 3' untranslated region of the virus RNA. It is sugge sted that the inhibitory effect of these novel modified oligonucleotid es is due to their increased affinity for the target sequences and tha t they probably function via an RNase H cleavage of the oligonucleotid e:RNA heteroduplex.