ENHANCEMENT OF ANTIHERPETIC ACTIVITY OF ANTISENSE PHOSPHOROTHIOATE OLIGONUCLEOTIDES 5'-END MODIFIED WITH GERANIOL

We have previously shown that antisense phosphorothioate oligonucleoti de (SON) targeted against immediate early (IE) pre-mRNA5 of the herpes simplex virus type I (HSV-1) possessed potent anti-herpetic activitie s in vitro system. However, anti-herpetic activities of SON were not s till efficient enough. Lipophilic compounds have been often conjugated with antisense oligonucleotide to enhance the biological activity. In this study, we selected geraniol as a lipophilic compound and newly s ynthesized SON bearing 5' terminal geraniol (geranyl-SON) toward LE pr e-mRNA 5 of the HSV-1 to enhance the anti-herpetic activity. Geraniol is a olefinic terpene alcohol which is found in many essential oils. I t possesses lipophilic characteristic. It is thought to be absorbed in tissue. Geraniol enhanced the anti-herpetic activity of SON with less cytotoxicity in a sequence specific manner. Terminal modification wit h geraniol did not affect binding affinity with complimentary DNA. Cyt oplasm distribution of geranyl-SON was confirmed by confocal microscop e. While some of the geranyl-SON was seen in the nucleus, unmodified S ON had a punctate distribution in the cytoplasm with little in the nuc leus. These results suggested that geranyl modification enhances anti- herpetic activity by changing the subcellular distribution of the olig onucleotides. Consequently geraniol-modifica-tion could provide new me ans for the efficient delivery of oligo-nucleotides.