Comparison of the effects of arabinosyladenine, arabinosylhypoxanthine, and arabinosyladenine 5'-monophosphate against herpes simplex virus, varicella-zoster virus, and cytomegalovirus with their effects on cellular deoxyribonucleic acid synthesis

Thymidine analogs highly active against herpes simplex virus were compared in their inhibitory action against seven strains of varicella-zoster virus by a plaque reduction assay. E-5-Bromovinyl-arabinosyluracil (BV-ara-U) was most active, followed by E-5-chlorovinyl-arabinosyluracil, E-5-bromovinyl-2'-deoxyuridine (BV-dUrd), 2'-fluoro-5-methyl-arabinosyluracil, 2'-fluoro-5-iodo-arabinosylcytosine, arabinosylthymine, 5-vinyl-arabinosyluracil, acycloguanosine, and 5-iodo-2'-deoxyuridine, in order of decreasing activity. BV-ara-U was more than 10 times as active as BV-dUrd and almost completely inhibited plaque development of five strains of varicella-zoster virus at a concentration as low as 1 ng/ml.Infection with varicella-zoster virus (VZV), a member of the human herpesvirus group, in normal individuals is generally a self-resolving, uncomplicated disease. However, complications resulting from VZV infection can be severe to life threatening in immunocompromised patients (5,14,17). It is necessary to develop nontoxic and effective antiviral agents for treatment of severe VZV infection. The object of this paper is to show that 1-P-D-arabinofuranosyl-E-5-bromovinyluracil (BV-ara-U) and 1-,B-D-arabinofuranosyl-E-5-chlorovinyluracil (CV-ara-U) were extraordinarily active against seven strains of vzv.Human embryonic lung fibroblast (HEL-F) cells were used in this study. Methods for cultivation of the cells were described previously (10). VZV strains YS and Asahikawa were kindly supplied by T. Sakuma, Asahikawa Medical College, Asahikawa, Japan; strains Oka and Kawaguchi were supplied by M. Takahashi,

supporting

confidence: 80%

Inhibitory effects of antiherpesviral thymidine analogs against varicella-zoster virus

Machida¹,

Kuninaka²,

Yoshino³

1982

“…Our data indicate also that there is no strain-dependent difference in antiviral drug susceptibility between the KMcC and Oka strains of V-Z vaccine virus. Since our EDs are generally consistent with those of other authors who tested either lower-passaged virus (15,16,22,30) or a larger number of different strains (4,8,9,12,15,17,22,30), a general conclusion appears to be that susceptibility of V-Z virus to the antiviral compounds tested is not significantly altered by changes in passage level or strain. With respect to other strains of V-Z virus, one would expect BVDU and FIAC or ACV and Ara-A to be of comparable in vitro potency, the former two, however, being far more active than the latter two.…”

Section: Resultssupporting

confidence: 77%

“…Since there are no data suggesting that simple tissue culture passage results in the development of thymidine kinase-deficient mutants, it is not surprising that the high-passage KMcC virus and the Oka vaccine virus were no less susceptible than their low-passage counterparts were to ACV (6,15,30), BVDU (15,30), and FIAC (21). The activity of DNA polynierase was also not affected, as evidenced by the equal susceptibility of viruses of different passage levels to Ara-A (11,17), PFA (19,33), and aphidicolin (3,10,25), which specifically inhibits a-polymerase. Our data indicate also that there is no strain-dependent difference in antiviral drug susceptibility between the KMcC and Oka strains of V-Z vaccine virus.…”

Section: Resultsmentioning

confidence: 99%

Susceptibility of vaccine strains of varicella-zoster virus to antiviral compounds

Preblud¹,

Arbeter²,

Proctor³

et al. 1984

Using a plaque reduction assay, we determined the 50% effective doses of six antiviral compounds against low-and high-passage viruses of the KMcC and Oka strains of varicella-zoster virus vaccine. The potency, as indicated by the ranges of 50% effective doses (micrograms per milliliter) of the antiviral compounds, in decreasing order was as follows: (E)-5-(2-bromovinyl)-2'-deoxyuridine, 0.0007 to 0.0035; 1-(2'-flouro-2-deoxy-p-D-arabinofuranosyl)-5-iodocytosine, 0.0063 to 0.0091; aphidicolin, 0.092 to 0.180; acyclovir, 0.79 to 1.81; vidarabine, 0.62 to 2.10; and phosphonoformic acid, 8.18 to 16.4. Susceptibility to the various antiviral compounds was independent of passage level or strain. These data, along with the available in vivo data, indicate that varicella-zoster virus vaccine infections requiring antiviral therapy most probably would be treated as effectively as would natural varicella infections.The success of Japanese investigators in immunizing large numbers of normal and immunosuppressed children and adults with a live attenuated varicella-zoster (V-Z) virus vaccine over the past decade (31, 32) has led to vaccine field trials in this country (1,2,7,18,24). Two vaccine strains have been used: the KMcC strain, passed 10 to 60 times in WI-38 cells (1,24), and the Japanese or Oka strain, passed 11 times in human embryo fibroblasts, 12 times in guinea pig embryo cells, and an additional 1 to 21 times in human diploid cells (2,7,18,31,32). To date the vaccines have been shown to be safe, immunogenic, and effective. However, with the immunization of increasing numbers of leukemics, severe infections due to vaccine may necessitate treatment with an antiviral drug, as discussed at a recent workshop on V-Z virus vaccine held at the National Institutes of Health in September 1983. The current experience in treating wildtype V-Z virus infections with arabinosyladenine (9-4-Darabinofuranosyladenine, vidarabine, or Ara-A) (35, 36), acyclovir {9-[(2-hydroxyethoxy)methyl]guanine, acycloguanosine, or ACV} (26,29), and E-5-(2-bromovinyl)-2'-deoxyuridine (bromovinyldeoxyuridine, or BVDU) (14), as well as the available data on the in vitro susceptibility of the Oka vaccine strain (15,22,30), suggests that these three compounds would be therapeutically effective. Favorable results with ACV were discussed at the National Institutes of Health workshop. There are, however, no published data on the in vitro susceptibility of the KMcC strain of vaccine virus.We determined the 50 and 90% effective doses (ED5os and ED90s, respectively) of six antiviral drugs against low-and high-passage KMcC strain viruses with a plaquie reduction assay (16,27). Aphidicolin, a tetracyclic diterpene-tetraol produced by Cephalosporium aphidicola (10, 25), was included in this group. This compound is a specific a-polymerase inhibitor and is effective in vitro against herpes simplex virus (3, 10, 25) and cytomegalovirus (E. Gonczol, personal communication). The activity of aphidicolin againt V-Z virus is, to the best of our knowledge, untested....

“…Neplanocin C was, in general, equally cytotoxic but less potent than neplanocin A. If for each cell system (Tables 1 through 3), the lowest minimum cytotoxic concentrations were compared to the lowest minimum antiviral concentrations ( with previous findings that hypoxanthine derivatives are, as a rule, less potent antiviral agents than their adenine counterparts, i.e., hypoxanthine arabinoside versus adenine arabinoside (4,12,20), formycin B versus formycin A (13) and 9-(2,3-dihyroxypropyl)hypoxanthine versus 9-(2,3-dihydroxypropyl)adenine (9).…”

Section: Discussionmentioning

confidence: 99%

Antiviral and antimetabolic activities of neplanocins

Clercq¹

1985

217

108

Of a series of carbocyclic analogs of adenosine, in which the ribose moiety was replaced by a cyclopentenyl ring, neplanocin A, or (-)-9-[trans-2, trans-3-dihydroxy-4-(hydroxymethyl)cyclopent-4-enyl]adenine proved particularly effective in inhibiting the multiplication of DNA viruses (i.e., vaccinia), (-)RNA viruses (i.e., parainfluenza, measles, and vesicular stomatitis), and double-stranded RNA viruses (i.e., reo) in vitro in cell culture. Depending on the cells used, the MIC of neplanocin A for these viruses ranged from 0.01 to 4 micrograms/ml, and depending on the parameter used to assess toxicity for the host cell, the specificity index of neplanocin A ranged from 50 to 4,000. As postulated before for other adenosine analogs, neplanocin A may owe its antiviral action to inhibition of S-adenosylhomocysteine hydrolase, hence perturbation of transmethylation reactions. In vivo, neplanocin A afforded only marginal protection against a lethal infection of mice with vesicular stomatitis virus.