2'-fluoro-5-iodo-aracytosine, a potent and selective anti-herpesvirus agent

The selectivity of inhibition of herpesvirus deoxyribonucleic acid synthesis by acycloguanosine, 2'-fluoro-5-iodo-aracytosine, and (E)-5-(2-bromovinyl)-2'-deoxyuridine was determined by isopycnic banding of 32P-labeled deoxyribonucleic acid from herpesvirus-infected and uninfected cells.An important property of an antiviral compound is the selectivity of its action. Most compounds with a high activity against herpesviruses are nucleoside analogs (3,8,9,11 press). To measure both viral and cellular DNA synthesis, nonconfluent cell cultures and a low multiplicity of infection were used. The selective action of acycloguanosine (ACG), 2'-fluoro-5-iodoaracytosine (FIAC), and (E)-5-(2-bromovinyl)-2'-deoxyuridine (BrVDU) on viral and cellular DNA synthesis in herpes simplex virus type 1 (HSV-1)-infected and uninfected Vero cells has been determined by isopycnic banding of DNA in CsCl gradients. These nucleosides have previously shown a high antiherpes activity (1,5,10,12,13) and are also known to require the presence of herpesvirus-induced thymidine kinase for their antiviral activity (2, 5, 10).ACG showed a high selectivity in the inhibition of viral DNA synthesis ( Fig. 1A to C; Table 1). When viral DNA synthesis was inhibited by 90% at 0.3 uM, only 15% inhibition of cellular DNA synthesis was observed. No effect on DNA synthesis in uninfected cells could be detected at this concentration and 310 ,M ACG was required for a 50% inhibition. The high selectivity found for ACG correlates well with earlier results showing that ACG is phosphorylated to a much higher extent to its mono-, di-, and triphosphate in HSV-1-infected celis than in uninfected cells and that ACG triphosphate is selectively accepted by HSV-1 DNA polymerase, leading to chain termination (5, 7).FIAC was less selective than ACG in the inhibition of viral DNA synthesis in infected cells ( Fig. 1D to F; Table 1). At 0.10 ,uM a 90% inhibition of viral DNA synthesis was obtained, whereas cellular DNA synthesis in infected cells was inhibited by 40%. However, DNA synthesis in uninfected cells was not inhibited at this concentration, and 64 ,LM FIAC was required to obtain a 50% inhibition, which confirms the results of Lopez et al. (10) showing a high selectivity by FIAC when effects on HSV-1 multiplication and cytotoxicity for uninfected Vero cells were compared.BrVDU inhibited viral DNA synthesis by 90% at a concentration of 0.6 uM ( Fig. 1G to I; Table 1). As in the case of FIAC, but not of ACG, the cellular DNA synthesis in infected cells was also affected, to 60%, at this concentration. In the uninfected cells, DNA synthesis was not affected by 0.6 juM BrVDU, and at 440 ,M a 50% inhibition was observed. These results agree with those of De Clercq et al. (1), who have shown previously that BrVDU inhibits HSV-1 multiplication at low concentrations, while not affecting the growth of uninfected cells.In a cell-free assay, BrVDU seems to be selectively phosphorylated by HSV-1 thymidine kinase (A. Larsson, unpublished data

supporting

confidence: 78%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Selective Inhibition of Herpesvirus Deoxyribonucleic Acid Synthesis by Acycloguanosine, 2′-Fluoro-5-Iodo-Aracytosine, and ( E )-5-(2-Bromovinyl)-2′-Deoxyuridine

Larsson

Öberg

1981

“…Addition of equimolar concentrations of thymidine failed to reverse the antiviral activity and had no significant effect on the cytotoxicity (data not shown). A 10-fold excess of the thymidine failed to reverse the antiviral activity of FIAC and at higher concen- Our earlier studies showed that herpes simplex virus type 1-induced pyrimidine nucleoside kinase was capable of phosphorylating FIAC far better than the cellular enzymes and that this substrate preference determined, at least in part, the selective antiviral activity of this drug (18). Studies were therefore undertaken to determine whether FIAC is preferentially phosphorylated by enzymes found in cytosols from HCMVinfected rather than uninfected cells.…”

Section: Resultsmentioning

confidence: 99%

Efficacy and selectivity of some nucleoside analogs as anti-human cytomegalovirus agents

Colacino¹,

López²

1983

Self Cite

(FEAU) were evaluated for antiviral activities against human cytomegalovirus (HCMV) and compared with 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir) and E-5-(2'-bromovinyl)-2'-deoxyuridine (BVDU). The relative anti-HCMV potencies of these compounds, as determined by calculating the dose of drug which inhibited 50% plaque formation, were in order of decreasing potency: FIAC > FIAU > FMAU > acyclovir > FEAU > BVDU. The antiviral activity of FIAC occurred at levels much lower than those that caused cytotoxic or cytostatic effects in uninfected fibroblasts. Neither thymidine nor deoxycytidine reversed the anti-HCMV activity of FIAC, indicating that this drug was not acting as an analog of the natural nucleosides. FIAC was not phosphorylated by cytosols of HCMV-infected cells to a greater extent that by those of uninfected cells, indicating that, unlike the antiviral activity against herpes simplex virus type 1, the selectivity of this drug is probably not based on a virus-specified pyrimidine kinase.

“…The clinical management of herpes simplex virus (HSV) infections has become more effective in recent years with the introduction of selective anti-HSV drugs, such as acyclovir [9-(2-hydroxyethoxymethyl)guanine; ACV], E-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), and 2'-fluoro-5-iodo-1-P-Darabinofuranosylcytosine (FIAC) (11,14,35). These drugs inhibit the replication of HSV in vitro and in vivo, while manifesting little or no toxicity.…”

mentioning

confidence: 99%

Nucleotide sequence changes in thymidine kinase gene of herpes simplex virus type 2 clones from an isolate of a patient treated with acyclovir

Kit

Sheppard

Ishiguro

et al. 1987

To identify the nucleotide changes that occur in drug-induced thymidine kinase (TK) mutants of herpes simplex virus type 2 (HSV-2), we compared the nucleotide sequences of the tk genes of two mutant HSV-2 clones isolated from a patient who had been treated with acyclovir [9-(2-hydroxyethoxymethyl) was the same as that of the laboratory strain, TK+ HSV-2(333). The nucleotide sequence of a bromodeoxyuridine-resistant TK-HSV-2(333) mutant of TK+ HSV-2(333) also exhibited a single-base deletion, but at nucleotide 439. This deletion would cause a frameshift mutation at amino acid residue 147 and chain termination at amino acid residue 182. The frameshift mutations of TK-HSV(8710) and TK-HSV-2(333), respectively, occurred in sequences in which C was repeated three times and G was repeated seven times. The results raise the possibility that TK-frameshift mutations of HSV-2 may be common.