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Enhancement of anti-herpetic activity of antisense phosphorothioate oligonucleotides 5' end modified with geraniol. 1998

Y Shoji, and H Ishige, and N Tamura, and W Iwatani, and M Norimatsu, and J Shimada, and Y Mizushima
Institute of Medical Science, St. Marianna University, School of Medicine, Kawasaki, Japan. cat05095@catline.or.jp

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.

UI MeSH Term Description Entries
D002522 Chlorocebus aethiops A species of CERCOPITHECUS containing three subspecies: C. tantalus, C. pygerythrus, and C. sabeus. They are found in the forests and savannah of Africa. The African green monkey is the natural host of SIMIAN IMMUNODEFICIENCY VIRUS and is used in AIDS research. African Green Monkey,Cercopithecus aethiops,Cercopithecus griseoviridis,Cercopithecus griseus,Cercopithecus pygerythrus,Cercopithecus sabeus,Cercopithecus tantalus,Chlorocebus cynosuros,Chlorocebus cynosurus,Chlorocebus pygerythrus,Green Monkey,Grivet Monkey,Lasiopyga weidholzi,Malbrouck,Malbrouck Monkey,Monkey, African Green,Monkey, Green,Monkey, Grivet,Monkey, Vervet,Savanah Monkey,Vervet Monkey,Savannah Monkey,African Green Monkey,Chlorocebus cynosuro,Green Monkey, African,Green Monkeys,Grivet Monkeys,Malbrouck Monkeys,Malbroucks,Monkey, Malbrouck,Monkey, Savanah,Monkey, Savannah,Savannah Monkeys,Vervet Monkeys
D004247 DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA, Double-Stranded,Deoxyribonucleic Acid,ds-DNA,DNA, Double Stranded,Double-Stranded DNA,ds DNA
D000080462 Acyclic Monoterpenes Linear compounds that contain a single monoterpene unit. Monoterpenes, Acyclic
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000998 Antiviral Agents Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. Antiviral,Antiviral Agent,Antiviral Drug,Antivirals,Antiviral Drugs,Agent, Antiviral,Agents, Antiviral,Drug, Antiviral,Drugs, Antiviral
D001483 Base Sequence The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence. DNA Sequence,Nucleotide Sequence,RNA Sequence,DNA Sequences,Base Sequences,Nucleotide Sequences,RNA Sequences,Sequence, Base,Sequence, DNA,Sequence, Nucleotide,Sequence, RNA,Sequences, Base,Sequences, DNA,Sequences, Nucleotide,Sequences, RNA
D013347 Subcellular Fractions Components of a cell produced by various separation techniques which, though they disrupt the delicate anatomy of a cell, preserve the structure and physiology of its functioning constituents for biochemical and ultrastructural analysis. (From Alberts et al., Molecular Biology of the Cell, 2d ed, p163) Fraction, Subcellular,Fractions, Subcellular,Subcellular Fraction
D013729 Terpenes A class of compounds composed of repeating 5-carbon units of HEMITERPENES. Isoprenoid,Terpene,Terpenoid,Isoprenoids,Terpenoids
D013873 Thionucleotides Nucleotides in which the base moiety is substituted with one or more sulfur atoms.
D014709 Vero Cells A CELL LINE derived from the kidney of the African green (vervet) monkey, (CHLOROCEBUS AETHIOPS) used primarily in virus replication studies and plaque assays. Cell, Vero,Cells, Vero,Vero Cell

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