Vmw65 phosphorothioate oligonucleotides inhibit HSV KOS replication and Vmw65 protein synthesis.
Phosphorothioate-modified oligomers have been shown to be more stable than natural oligomers to serum and cellular nucleases. For this reason we used these analogs to explore the utility of antisense molecules as potential antiviral agents. The oligomers we studied are complementary to the initiation region of the Vmw65 (alpha-TIF) gene of HSV-1 which is important both for its structural role and in the transactivation of the alpha genes of HSV. Our results demonstrate that Vmw65-specific oligomers inhibit HSV KOS replication in a dose-dependent manner from 25 micrograms/ml (4.3 microM) to 50 ng/ml (9 nM). Vmw65 protein synthesis is inhibited from 51 to 68% at 5 micrograms/ml (0.8 microM) using Vmw65-specific oligomers 293s and 432s respectively. A random AT-rich oligomer, 007s, inhibited HSV KOS replication in a non-dose-dependent manner. Inhibition was only observed at a concentration of 12.5 micrograms/ml (2.1 microM) or more, using an MOI (multiplicity of infection) of 0.05 PFU/cell and a 24-h post-infection harvest.
Kmetz
M E
ME
Department of Antiviral Chemotherapy, Schering-Plough Corporation, Bloomfield, New Jersey.
Ceruzzi
M
M
Schwartz
J
J
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D015870:Gene Expression; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011233:Precipitin Tests; D018139:Simplexvirus / Q000187:drug effects* / Q000502:physiology; D013873:Thionucleotides / Q000494:pharmacology*; D015534:Trans-Activators / Q000096:biosynthesis*; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D015534:Trans-Activators