brivudine and fiacitabine

The molecular basis for the antiviral activity is discussed for a variety of nucleoside compounds approved for clinical use in the U.S.A. (5-iodo-2'-deoxyuridine, 5-trifluoromethyl-2'-deoxyuridine, 9-beta-D-arabinofuranosyladenine, 9-(2-hydroxyethoxymethyl)guanine), or in clinical trial (E-5-(2-bromovinyl)-2'-deoxyuridine, 1-(2-deoxy-2-fluoro-beta-D-arabinosyl)-5-iodocytosine, 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), or of specific interest to our laboratory (5-iodo-5'-amino-2',5'-dideoxyuridine, 5'-amino-5'-deoxythymidine). The consequence of incorporation of idoxuridine, the 5'-amino analog of thymidine or the 5'-amino analog of idoxuridine into the DNA of herpes simplex virus type 1 on transcription and translation is emphasized.

Topics: Acyclovir; Antiviral Agents; Bromodeoxyuridine; Cytarabine; Dideoxynucleosides; DNA, Viral; Idoxuridine; Protein Biosynthesis; Ribavirin; Simplexvirus; Structure-Activity Relationship; Thymidine; Thymine Nucleotides; Transcription, Genetic; Vidarabine

In recent years several selective antiherpes drugs have been developed which all show great promise for the systemic and topical treatment of herpes simplex virus and varicella-zoster virus infections. These new antiherpes agents include acyclovir, bromovinyldeoxyuridine, fluoroiodoaracytosine and phosphonoformate. Acyclovir has already been licensed for both topical and systemic use, and it is expected that other compounds will follow soon. Although this new generation of antiherpes drugs suffer from some drawbacks, i.e. narrow spectrum of activity, inefficacy during virus latency, and the possible emergence of drug-resistant virus strains, these limitations by no means outweigh the potentials of these drugs in the therapy and prophylaxis of herpesvirus infections in humans.

Topics: Acyclovir; Antiviral Agents; Bromodeoxyuridine; Cytarabine; Drug Resistance, Microbial; Herpesviridae Infections; Humans; Kinetics; Nucleic Acid Synthesis Inhibitors; Vidarabine

A large number of nucleoside analogues have been found to have antiviral activity, mainly against herpesviruses. The involvement of cellular as well as viral enzymes in the mode of action of several nucleoside analogues makes a prediction of clinical efficacy difficult. The possibility and consequences of incorporation into cellular DNA are other important aspects of nucleoside analogues as antiviral drugs. It seems likely that in the next few years enough knowledge about mechanism of action, consequences of incorporation into DNA, efficacy in different test systems and in clinical trials will accumulate to allow an understanding of how to design even better antiviral drugs.

Topics: Acyclovir; Animals; Antiviral Agents; Biotransformation; Bromodeoxyuridine; Cytarabine; DNA-Directed RNA Polymerases; Ganciclovir; Humans; Idoxuridine; Nucleic Acid Synthesis Inhibitors; Nucleic Acids; Nucleosides; Ribavirin; Trifluridine; Vidarabine; Viruses

Topics: Acyclovir; Adenine; Animals; Antiviral Agents; Arabinonucleosides; Bromodeoxyuridine; Chemical Phenomena; Chemistry; Cytarabine; Deoxyuridine; Guanine; Herpesviridae Infections; Humans; Idoxuridine; Nucleosides; Ribavirin; Thymidine; Virus Diseases; Viruses

The susceptibilities of gammaherpesviruses, including Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and animal rhadinoviruses, to various nucleoside analogs was investigated in this work. Besides examining the antiviral activities and modes of action of antivirals currently marketed for the treatment of alpha- and/or betaherpesvirus infections (including acyclovir, ganciclovir, penciclovir, foscarnet, and brivudin), we also investigated the structure-activity relationship of various 5-substituted uridine and cytidine molecules. The antiviral efficacy of nucleoside derivatives bearing substitutions at the 5 position was decreased if the bromovinyl was replaced by chlorovinyl. 1-β-D-Arabinofuranosyl-(E)-5-(2-bromovinyl)uracil (BVaraU), a nucleoside with an arabinose configuration of the sugar ring, exhibited no inhibitory effect against rhadinoviruses but was active against EBV. On the other hand, the fluoroarabinose cytidine analog 2'-fluoro-5-iodo-aracytosine (FIAC) showed high selectivity indices against gammaherpesviruses that were comparable to those of brivudin. Additionally, we selected brivudin- and acyclovir-resistant rhadinoviruses in vitro and characterized them by phenotypic and genotypic (i.e., sequencing of the viral thymidine kinase, protein kinase, and DNA polymerase) analysis. Here, we reveal key amino acids in these enzymes that play an important role in substrate recognition. Our data on drug susceptibility profiles of the different animal gammaherpesvirus mutants highlighted cross-resistance patterns and indicated that pyrimidine nucleoside derivatives are phosphorylated by the viral thymidine kinase and purine nucleosides are preferentially activated by the gammaherpesvirus protein kinase.

Topics: Acyclovir; Amino Acid Sequence; Animals; Antiviral Agents; Arabinofuranosyluracil; Bromodeoxyuridine; Cytarabine; DNA-Directed DNA Polymerase; Drug Resistance, Viral; Foscarnet; Ganciclovir; Guanine; Herpesvirus 4, Human; Herpesvirus 8, Human; Humans; Molecular Sequence Data; Protein Kinases; Rhadinovirus; Sequence Alignment; Structure-Activity Relationship; Thymidine Kinase; Viral Proteins

The 2'-fluoropyrimidine nucleoside analogs 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC). 1(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-methyluracil (FMAU), and 1(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (FIAU) showed higher in vitro activity against herpes simplex virus type 1 (HSV-1), than equine herpesvirus 1 (EHV-1) or pseudorabies virus (PRV). Comparison of the 50% plaque inhibitory doses for HSV-1 and its mutant MMdUr-20 in cell cultures with inhibition constants (Ki's) for the viral deoxythymidine kinases (dTKs) suggests that in the infected cell FMAU is phosphorylated by host enzymes. As compared to HSV-1, EHV-1 and PRV were more resistant to E-5-(2-bromovinyl-2'-deoxyuridine (BVdU) and to the 2'-fluoropyrimidine analogs, as are HSV-2 and the HSV-1 mutants MMdUr-20 and S1. Because the dTKs of the latter lack deoxythymidylate kinase (dTMPK) activity, there appears to be a correlation between resistance to these analogs and BVdU on the one hand, and lack of dTMPK activity on the other. We predict that EHV-1 and PRV dTKs will be shown to lack significant dTMPK activity.

Topics: Animals; Antiviral Agents; Arabinofuranosyluracil; Bromodeoxyuridine; Cytarabine; Drug Resistance, Microbial; Herpesviridae; Herpesvirus 1, Suid; Horses; Nucleoside-Phosphate Kinase; Pseudorabies; Pyrimidine Nucleosides; Substrate Specificity

A decrease in the in vitro sensitivity to acyclovir (ACV) was observed in successive isolates of herpes simplex virus type 1 from three immunocompromised patients during intravenous therapy with this drug. The ACV-resistant isolate from patient 1 was cross-resistant to dihydroxypropoxymethylguanine and bromovinyldeoxyuridine, but still susceptible to three fluoro-substituted pyrimidines, 2'-fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine (FIAC), 2'-fluoro-5-iodo-1-beta-D-arabinofuranosyluracil (FIAU), and 2'-fluoro-5-iodo-1-beta-D-arabinofuranosylthymine (FMAU). The thymidine kinase (TK) from the resistant isolate showed a 50-fold or greater reduction in affinity for thymidine, FIAU, FMAU, and ACV, but the total enzyme activity was similar to that of the sensitive isolate. The ACV-resistant isolate from patient 2 was also resistant to dihydroxypropoxymethylguanine, bromovinyldeoxyuridine, and the fluoro-substituted compounds; TK activity for this isolate was less than 1% of the patient's pretherapy isolate. An isolate obtained during a subsequent recurrence in patient 2 was susceptible to ACV and the other TK-dependent agents. The ACV-resistant isolate from patient 3 was partially resistant to FIAC and FIAU but still susceptible to FMAU; the viral TK had a 10-fold-lower affinity for ACV, FIAU, and FMAU than did the sensitive pretherapy isolate, while the level of TK activity detected was reduced to 6%. In none of the isolates studied was a change in sensitivity to phosphonoformic acid observed. Compared with the corresponding pretherapy ACV-sensitive isolates, there was a 30-fold decrease in neurovirulence for mice of the two drug-resistant isolates with diminished levels of thymidine-phosphorylating activity and no change in virulence for the third isolate. These findings indicate that mixed patterns of drug-resistance to TK-dependent antiviral compounds can occur in clinical isolates, resulting from changes in either the amount or the affinity of viral TK activity.

Topics: Acyclovir; Adult; Animals; Antiviral Agents; Arabinofuranosyluracil; Bromodeoxyuridine; Cytarabine; Drug Resistance, Microbial; Female; Ganciclovir; Humans; Male; Mice; Mice, Inbred BALB C; Simplexvirus; Stomatitis, Herpetic; Thymidine Kinase; Virulence

The effect of several antiviral drugs on the reactivation of herpes simplex virus type 1 in explant cultures of latently infected mouse trigeminal ganglia was investigated. Phosphonoacetate and phosphonoformate, which act directly on the virus-induced DNA polymerase, require a drug concentration of 400 micrograms/ml for the inhibition of virus reactivation in latently infected ganglia. Arabinosyladenine and arabinosyladenine monophosphate, which are phosphorylated to triphosphates by cellular enzymes and inhibit virus synthesis either by blocking the DNA polymerase or by incorporation into viral DNA, require a concentration of only 100 micrograms/ml for the inhibition of the reactivation process. Drugs that are phosphorylated by the virus-induced thymidine kinase, such as acyclovir, arabinosylthymine, bromovinyldeoxyuridine, and three fluorinated pyrimidine nucleosides require the lowest drug concentrations for complete inhibition of virus reactivation in latently infected ganglia explant cultures. Our data suggest that the inhibition of virus reactivation is dependent not only on drug concentration, but also on the number of latently infected neurons in the ganglia.

Topics: Acyclovir; Animals; Antibodies, Viral; Antiviral Agents; Arabinofuranosyluracil; Arabinonucleosides; Bromodeoxyuridine; Culture Media; Culture Techniques; Cytarabine; Foscarnet; Mice; Mice, Hairless; Neutralization Tests; Phosphonoacetic Acid; Simplexvirus; Thymidine; Trigeminal Nerve; Vidarabine Phosphate; Virus Activation

Epstein-Barr virus (EBV) is the cause of infectious mononucleosis and is associated with three human malignancies. Acyclovir [9-(2-hydroxyethoxymethyl)guanine], the first clinically useful drug effective against replication of EBV, is without effect against latent or persistent EBV infection. Three nucleoside analogs, E-5-(2-bromovinyl)-2'-deoxyuridine, 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine, and 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-methyluracil are potent inhibitors of EBV replication in vitro. Moreover, in contrast to the reversibility of viral inhibition by Acyclovir, these three drugs have prolonged effects in suppressing viral replication even after the drugs are removed from persistently infected cell cultures.

Topics: Acyclovir; Antiviral Agents; Arabinofuranosyluracil; Bromodeoxyuridine; Cytarabine; DNA Replication; Herpesvirus 4, Human; Uridine; Virus Replication

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 (32)P-labeled deoxyribonucleic acid from herpesvirus-infected and uninfected cells.

Topics: Acyclovir; Animals; Antiviral Agents; Bromodeoxyuridine; Cell Line; Chlorocebus aethiops; Cytarabine; DNA; DNA, Viral; Guanine; Kidney; Simplexvirus