Inhibition of herpes simplex virus type 2 growth by phosphorothioate oligodeoxynucleotides

Abstract

Phosphorothioate homo-oligodeoxynucleotides were found to be potent inhibitors of herpes lvus type 2 (HSV-2) but less potent for HSV-1 in cell culture studies. Oligomers with longer chain lengths were more active against HSV-2 than those with shorter ones. Of all the compounds examined, the 28-mer phosphorothioate homo-oligodeoxynucleotides were the strongest inhibitors of HSV-2. The degree of inhibition was relited to the base moiety on the order of deoxycytidiie = thymidine > deoxyadenosine. The inhibition of HSV-2 growth by S-dC23 was dose dependent with a 90% inhibitory dose of 1 FLM. At 50 FM, S-dC2 inhibited HeLa S3 cell growth by less than 10%. The anti-HSV-2 activity was time and schedule dependent. The oligomer wu most inhibitory to viral growth when present during the 1-h viral adso*ption period, and this effect could -be enhanced by continuous drug exposure after the adsorption period. S-dC23 was also an effective inhibitor of two HSV-2 drug-resistant mutants: a phosphonoformate-reistant mutant that induces an altered DNA polymerase and a 9-(1,3-dihydroxy-2-propoxymethyl)guanine-resistant mutant that does not induce the viral thymidine kinase. In drug combination studies, phosphonoformate was shown to potentiate the action of S4C2 against HSV-2 growth. In condusion, because of their potency and selectivity, phosphorothioate homo-oligedeoxynucleotides are a promising new class of anti-HSV agents.

Inhibition of High Affinity Basic Fibroblast Growth Factor Binding by Oligonucleotides

“…The action of oligonucleotides against herpes simplex virus and human cytomegalovirus have been reported previously (3,8,9), but the actual analysis of the data has been complicated by the ability of the oligonucleotides to operate on the exterior of the cell as inhibitors of viral adsorption. The binding of herpes simplex virus to the cell involves an initial attachment to cell surface heparan sulfate molecules and can be competed by the addition of heparin to the media (21).…”

“…Compounds are most often designed as antisense agents and, as such, have shown efficacy in cell culture and in some animal models of disease. Efficacious oligonucleotides have been used against viruses, including human cytomegalovirus, herpes simplex virus, human immunodeficiency virus, and papillomavirus, and against various cellular targets, including the oncogenes c-myc, c-myb, and c-abl (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). In addition investigators have used anti-cmyc/-myb antisense oligonucleotides to prevent restenosis in animal models (13)(14)(15).…”

Inhibition of Human Cytomegalovirus DNA Replication with a Phosphorothioate Cholesteryl-Modified Oligonucleotide is Mediated by Rapid Cellular Association and Virus-Facilitated Nuclear Localization

“…These experiments were done after a pretreatment with oligonucleotide. It has been reported that infection in the presence of oligonucleotide can increase uptake (Gao et al, 1990). The studies using fluorescein-conjugated oligonucleotide investigated the relative differences in uptake and subcellular distribution.…”

3'-Carbon-Substituted Pyrimidine Nucleosides Having a 2',3'-dideoxy and 2',3'-didehydro-2',3'-dideoxy Structure: Synthesis and Antiviral Evaluation

“…However, their 3′-carbon substituted analogues (d4U, 6-13; d4C, 22-28; ddC, 29-33) synthesized in the present study were found to be uniformly inactive. These compounds were also tested for their inhibitory activity against HBV (Doong et al, 1991), HSV-1 and HSV-2 (Cheng et al, 1980;Gao et al, 1990). Unfortunately, no appreciable antiviral activity was seen also against these viruses.…”