Antiviral activity of 5-ethyl-2'-deoxyuridine against herpes simplex viruses in cell culture, mice, and guinea pigs

Abstract

The susceptibility of 3 laboratory strains and 24 clinical isolates of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) to 5-ethyl-2'-deoxyuridine was determined in plaque reduction assays in Vero cells. The median effective doses were 8.6 and 7.8 ,M, respectively. The drug was less potent than acyclovir and other related antiviral drugs, but it had a high therapeutic index against both HSV-1 and HSV-2. Drug-resistant viruses were readily produced in cell culture. These variants were cross-resistant to acyclovir, 2'-fluoro-5-iodoaracytosine, and 2'-fluoro-5-methylarauracil but were susceptible to vidarabine or phosphonoformate. These findings confirm that the selective antiviral activity of 5-ethyl-2'-deoxyuridine is mediated by the virus-induced thymidine kinase. Oral or intraperitoneal administration of the drug at nontoxic doses was ineffective in protecting mice against intracerebral challenge with virus. Using implanted osmotic minipumps or coadministering the drug with dimethyl sulfoxide failed to decrease the mortality rate. In guinea pigs infected genitaily with HSV-2, topical drug treatment was more effective than placebo in reducing lesion severity and other clinical and virological variables. These effects were noted whether the drug treatment was initiated 3 or 24 h after infection (ascertained serologically). Drug-treated animals had a significantly lower herpes antibody titer than did placebo-treated guinea pigs, suggesting that the drug can also reduce the viral antigen load. In this model, the drug appeared to be as effective as topical phosphonoformate or acyclovir.5-Ethyl-2'-deoxyuridine (EdU) is a pyrimidine nucleoside with activity in cell culture against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) and vaccinia virus (9,16,28,48). The compound is also active in rabbits with herpes keratitis (13, 15), in mice with systemic herpetic infection (7,8), and in dorsally infected guinea pigs (46). Studies in humans have indicated positive effects with this drug for the treatment of ocular herpes (13, 35). EdU does not appear to interfere with regeneration of the epithelium of the rabbit eye (17). EdU has no demonstrable mutagenicity, and the drug does not induce RNA retroviruses in several cell culture systems (20,29,45,48). In rats, more than 90% of the drug or its metabolites are excreted in the kidney within 24 h (24).Since the full spectrum of activity of this drug against HSV is incomplete, several studies were initiated which had the following objectives: (i) delineating the activity of EdU against 2 laboratory strains and 12 clinical isolates of HSV-1 and 1 laboratory strain and 12 clinical isolates of HSV-2; (ii) comparing the cell culture activity of EdU with those of acyclovir (ACV), vidarabine (ara-A), E-5-(2-bromovinyl)-2'-deoxyuridine, 2'-fluoro-5-methylarauracil (FMAU), and 2'-fluoro-5-iodoaracytosine against laboratory strains of HSV; (iii) assessing activities of several of these agents against EdU-resistant variants; (iv) determining the capacity of EdU administered ...

Structure-activity relationships and conformational features of antiherpetic pyrimidine and purine nucleoside analogues. A review

“…Edoxudine is as effective as aciclovir (see below) in the topical treatment of HSV-I and HSV-2 infections in guinea-pigs [61]. It was licensed in Germany, as Aedurid | for the topical treatment of herpetic keratitis, and clinical trials have been initiated to establish its value in the topical treatment of genital herpes.…”