Enhancement of anti-herpetic activity of antisense phosphorothioate oligonucleotides 5' end modified with geraniol.
We have previously shown that antisense phosphorothioate oligonucleotide (SON) targeted against immediate early (IE) pre-mRNA5 of the herpes simplex virus type I (HSV-I) possessed potent anti-herpetic activities in vitro system. However, anti-herpetic activities of SON were not still 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 synthesized SON bearing 5' terminal geraniol (geranyl-SON) toward IE pre-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. It 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 with geraniol did not affect binding affinity with complimentary DNA. Cytoplasm distribution of geranyl-SON was confirmed by confocal microscope. While some of the geranyl-SON was seen in the nucleus, unmodified SON had a punctate distribution in the cytoplasm with little in the nucleus. These results suggested that geranyl modification enhances anti-herpetic activity by changing the subcellular distribution of the oligonucleotides. Consequently geraniol-modifica-tion could provide new means for the efficient delivery of oligo-nucleotides.
Institute of Medical Science, St. Marianna University, School of Medicine, Kawasaki, Japan. cat05095@catline.or.jp
Y
Y
Shoji
H
H
Ishige
N
N
Tamura
W
W
Iwatani
M
M
Norimatsu
J
J
Shimada
Y
Y
Mizushima
D000080462:Acyclic Monoterpenes; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D002522:Chlorocebus aethiops; D004247:DNA; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D018613:Microscopy, Confocal; D016376:Oligonucleotides, Antisense / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013347:Subcellular Fractions; D013729:Terpenes / Q000737:chemistry*; D013873:Thionucleotides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014709:Vero Cells
D000080462:Acyclic Monoterpenes; D000998:Antiviral Agents; D016376:Oligonucleotides, Antisense; D013729:Terpenes; D013873:Thionucleotides; D004247:DNA; C007836:geraniol