Inhibition of herpes simplex virus in culture by oligonucleotides composed entirely of deoxyguanosine and thymidine.
Oligodeoxynucleotides (ODNs) composed entirely of deoxyguanosine and thymidine, but not specifically designed to act as antisense agents, were able to significantly inhibit herpes simplex virus growth in acute infection assay systems. The guanosine/thymidine (GT) ODNs which demonstrated this antiviral activity contained either natural phosphodiester (PO) or phosphorothioate (PS) modified internucleoside linkages. In all experiments, the antiviral activity of the ODNs was enhanced when the backbone was modified to contain the PS linkages. When present during the time of virus addition, the ODNs were able to block the adsorption of virus to Vero cells. In this assay the PS-containing ODNs had ID50 values of approximately 0.020 microM for HSV-2 and of 0.3 microM for HSV-1. When these same PS-containing ODNs were used against HSV-2 in single-cycle viral yield assays, designed to minimize the effects due to external blockage of virus, the ID50 values rose to 0.2 microM. Analysis of viral DNA obtained 14 h post-HSV-2 infections in the single-cycle assay, revealed a decrease in replicated viral DNA in cells treated with PS-ODNs. Analysis of viral mRNA obtained 4 h post-HSV-2 infection revealed, in cells treated with the PS-ODNs, a decrease in measurable HSV-2 alpha- and beta-mRNAs. Although the mechanism of action of the antiviral activity (beyond adsorption blocking) is not fully understood, the toxicity of these compounds was low, giving high therapeutic indices for the GT-rich PS-ODNs. The good therapeutic index of GT-ODNs make this a class of compounds which warrant investigation as therapeutic agents to be used against herpes viruses.
Fennewald
S M
SM
Triplex Pharmaceutical Corporation, The Woodlands, TX 77380, USA.
Mustain
S
S
Ojwang
J
J
Rando
R F
RF
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000633:toxicity; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002522:Chlorocebus aethiops; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004279:DNA, Viral / Q000187:drug effects; D003849:Deoxyguanosine / Q000494:pharmacology* / Q000633:toxicity; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000494:pharmacology* / Q000633:toxicity; D012367:RNA, Viral / Q000187:drug effects; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D014709:Vero Cells
D000998:Antiviral Agents; D004279:DNA, Viral; D009841:Oligonucleotides; D012367:RNA, Viral; D003849:Deoxyguanosine; D013936:Thymidine