brivudine and penciclovir

During the last three decades, a better understanding of viral replication and disease states caused by viral infections have led to the development of newer antiviral agents with enhanced activity and better tolerability. This review focuses on newer systemic and topical antiviral agents that are used in treatment of herpes viruses including herpes simplex type-1 (HSV-1) and type-2 (HSV-2), varicella-zoster virus (VZV) and cytomegalovirus CMV) as well as the human papilloma virus (HPV). Included in this article are the agents famciclovir, penciclovir, valganciclovir, imiquimod, docosanole and brivudin.

Topics: 2-Aminopurine; Acyclovir; Aminoquinolines; Antiviral Agents; Bromodeoxyuridine; Famciclovir; Fatty Alcohols; Ganciclovir; Guanine; Humans; Imiquimod; Valganciclovir; Virus Diseases

The antiherpes drugs, aciclovir and ganciclovir, are considered the standard treatments and prophylactic agents for infections caused by herpes simplex virus (HSV), varicella zoster virus (VZV) and cytomegalovirus (CMV). Until a decade ago, the impact of aciclovir on the control of severe and life-threatening herpesvirus infections was unprecedented. During the past few years, we have witnessed approval of new therapeutic drugs for infections caused by HSV and VZV (i.e. penciclovir and the oral prodrugs, valaciclovir and famciclovir), CMV (i.e. ganciclovir, cidofovir and fomivirsen) or HSV, VZV and CMV (i.e. foscarnet). A few agents, such as brivudin and benzimidavir, are in ongoing clinical development; others have been suspended because of safety concerns. New antiherpes agents are needed to face clinical issues such as drug resistance, increased use of antiherpes prophylaxis in transplantation and safety concerns in small children or pregnant women.

Topics: 2-Aminopurine; Acyclovir; Antiviral Agents; Arabinofuranosyluracil; Bromodeoxyuridine; Cidofovir; Clinical Trials as Topic; Cytosine; Famciclovir; Foscarnet; Ganciclovir; Guanine; Herpesviridae Infections; Humans; Organophosphonates; Organophosphorus Compounds; Thionucleotides; Valacyclovir; Valine

A series of tricyclic penciclovir (PCV) and hydroxybutylguanine (HBG) derivatives have been prepared with enhanced lipophilicity following an efficient synthetic route. All the novel tricyclic derivatives were evaluated for inhibitory activity against herpes simplex virus 1 and 2 (HSV-1, HSV-2) and thymidine kinase deficient (ACV resistant) HSV-1. The tricyclic HBG derivatives were devoid of inhibitory activity however several of the tricyclic PCV derivatives showed promising antiviral activity, in particular 9g (R = 4-MeO-C

Topics: Acyclovir; Antiviral Agents; Guanine; Herpes Genitalis; Herpes Simplex; Herpesvirus 1, Human; Herpesvirus 2, Human; Humans; Models, Molecular

The role of mutations in the thymidine kinase (TK, UL23) and DNA polymerase (pol, UL30) genes of herpes simplex virus (HSV) for development of different resistance phenotypes has to be exactly determined before genotypic resistance testing can be implemented in patient's care. Furthermore, the occurrence of cross-resistance is of utmost clinical importance. In this study, clinical HSV-1 isolates obtained between 2004 and 2011 from 26 patients after stem cell transplantation were examined in parallel by phenotypic and genotypic resistance testing. Thirteen isolates, which were phenotypically cross-resistant to acyclovir (ACV), penciclovir (PCV) and brivudin (BVDU), exhibited consistently frameshift or non-synonymous mutations in the TK gene known to confer resistance. One of these mutations (insertion of C at the nucleotide positions 1061-1065) has not been described before. Seven strains, phenotypically resistant to ACV and PCV and, except one each, sensitive to BVDU and resistant to foscarnet (FOS), carried uniformly resistance-related substitutions in the DNA pol gene. Finally, 3 isolates, resistant to ACV, PCV and 2 out of these also resistant to BVDU, had known but also unclear substitutions in the TK and DNA pol genes, and 3 isolates were completely sensitive. In conclusion, clinical ACV-resistant HSV-1 isolates, carrying resistance-associated mutations in the TK gene, can be regarded as cross-resistant to other nucleoside analogs such as BVDU. In contrast, clinical FOS-resistant HSV-1 strains which are cross-resistant to ACV may be sensitive to BVDU. This has to be considered for drug changes in antiviral treatment in case of ACV resistance.

Topics: Acyclovir; Adolescent; Adult; Aged; Antiviral Agents; Bromodeoxyuridine; Child; DNA-Directed DNA Polymerase; DNA, Viral; Drug Resistance, Viral; Exodeoxyribonucleases; Female; Frameshift Mutation; Guanine; Herpes Simplex; Herpesvirus 1, Human; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mutagenesis, Insertional; Mutation, Missense; Point Mutation; Polymorphism, Single Nucleotide; Sequence Analysis, DNA; Thymidine Kinase; Viral Proteins; Young Adult

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

Studies to verify correlations between phenotypes and genotypes of herpes simplex virus (HSV) are an important tool to establish a database of resistance-associated mutations.. In this study, 32 acyclovir (ACV)-resistant clinical HSV-1 and 4 ACV-resistant clinical HSV-2 isolates were examined in parallel by both phenotypic and genotypic resistance testing. Additionally, five non-viable HSV-1 strains and two non-viable HSV-2 strains with clinical resistance were included in genotypic resistance analysis.. All ACV-resistant HSV isolates showed cross-resistance to brivudin and penciclovir, and were sensitive to foscarnet and cidofovir. Acyclovir resistance was assigned to frameshift and single non-synonymous mutations of the thymidine kinase (TK) gene in 32 out of 37 HSV-1 strains and in 4 out of 6 HSV-2 strains. In three HSV-1 isolates, there were resistance-associated amino acid substitutions of the DNA polymerase (pol). Six substitutions in the TK and two in the DNA pol gene could not be attributed without doubt to either ACV resistance or natural gene polymorphism. Altogether, 10 resistance-related mutations in the TK and 1 in the DNA pol gene have not been reported previously.. The novel non-synonymous mutations found in this study enrich the knowledge about the genetic alterations of TK and DNA pol genes in ACV-resistant clinical HSV strains. Together with data from the literature, the findings justify the generation of a HSV database that contains resistance mutations associated with ACV resistance phenotype.

Topics: Acyclovir; Adolescent; Adult; Aged; Antiviral Agents; Bromodeoxyuridine; Child; Child, Preschool; Cidofovir; Cytosine; DNA-Directed DNA Polymerase; Drug Resistance, Viral; Female; Foscarnet; Genotype; Guanine; Herpes Simplex; Herpesvirus 1, Human; Herpesvirus 2, Human; Humans; Infant; Male; Middle Aged; Mutation; Organophosphonates; Sequence Analysis, DNA; Thymidine Kinase; Viral Proteins

Sixteen herpes simplex virus type 1 (HSV-1) and four type 2 (HSV-2) isolates resistant to acyclovir (ACV) were characterized retrospectively for drug resistance. Phenotypic testing was performed by means of tetrazolium reduction assay and genotypic analysis was carried out by sequencing of thymidine kinase (TK) and DNA-polymerase (pol) genes. All strains were characterized as cross-resistant to penciclovir, brivudin and susceptible to cidofovir. In addition, three strains were resistant to foscarnet. Genotypic analysis revealed two to seven non-synonymous mutations in the TK gene of HSV-1 and one to seven non-synonymous mutations in the DNA pol gene of HSV-1 and 2 associated with the gene polymorphism. Seventeen strains contained at least one non-synonymous resistant-related mutation in the TK gene and three strains, which were additionally foscarnet-resistant, revealed one resistance-associated mutation in the DNA pol gene. In most strains, resistant-related mutations in TK gene represented frameshift mutations and single non-synonymous nucleotide substitutions of conserved gene regions. However, numerous amino acid changes could not be interpreted clearly as accounting for resistance. In conclusion, further studies, e.g. site-directed mutagenesis experiments are required to characterize mutations of the TK and DNA pol genes in ACV-resistant viral strains as part of viral gene polymorphism or as cause of drug resistance.

Topics: Acyclovir; Animals; Antiviral Agents; Bromodeoxyuridine; Cell Survival; Cells, Cultured; Cidofovir; Cytosine; DNA-Directed DNA Polymerase; Drug Resistance, Viral; Exodeoxyribonucleases; Foscarnet; Guanine; Herpesvirus 1, Human; Herpesvirus 2, Human; Humans; Microbial Sensitivity Tests; Mutation, Missense; Organophosphonates; Oxidation-Reduction; Sequence Analysis, DNA; Staining and Labeling; Tetrazolium Salts; Thymidine Kinase; Viral Proteins

Herpes B virus (B virus [BV]) is a macaque herpesvirus that is occasionally transmitted to humans where it can cause rapidly ascending encephalitis that is often fatal. To understand the low susceptibility of BV to the acyclonucleosides, we have cloned, expressed, and characterized the BV thymidine kinase (TK), an enzyme that is expected to "activate" nucleoside analogs. This enzyme is similar in sequence and properties to the TK of herpes simplex virus (HSV), i.e., it has a broad substrate range and low enantioselectivity and is sensitive to inhibitors of HSV TKs. The BV enzyme phosphorylates some modified nucleosides and acyclonucleosides and l enantiomers of thymidine and related antiherpetic analogs. However, the potent anti-HSV drugs acyclovir (ACV), ganciclovir (GCV), and 5-bromovinyldeoxyuridine were poorly or not phosphorylated by the BV enzyme under the experimental conditions. The antiviral activities of a number of marketed antiherpes drugs and experimental compounds were compared against BV strains and, for comparison, HSV type 1 (HSV-1) in Vero cell cultures. For most compounds tested, BV was found to be about as sensitive as HSV-1 was. However, BV was less sensitive to ACV and GCV than HSV-1 was. The abilities of thymidine analogs and acyclonucleosides to inhibit replication of BV in Vero cell culture were not always proportional to their substrate properties for BV TK. Our studies characterize BV TK for the first time and suggest new lead compounds, e.g., 5-ethyldeoxyuridine and pencyclovir, which may be superior to ACV or GCV as treatment for this emerging infectious disease.

Topics: Acyclovir; Amino Acid Sequence; Animals; Antiviral Agents; Chlorocebus aethiops; Deoxyuridine; Enzyme Inhibitors; Guanine; Herpesvirus 1, Cercopithecine; Microbial Sensitivity Tests; Molecular Sequence Data; Nucleosides; Phosphorylation; Substrate Specificity; Thymidine; Thymidine Kinase; Vero Cells

Varicella-zoster virus (VZV) mutants were isolated under the pressure of different classes of antiviral compounds: (i) drugs that depend on the viral thymidine kinase (TK) for their activation, i.e. acyclovir (ACV), brivudin (BVDU), penciclovir (PCV) and sorivudine (BVaraU); (ii) drugs that are independent of the viral TK for their activation, i.e. 2-phosphonylmethoxyethyl (PME) derivatives of adenine (PMEA, adefovir) and 2,6-diaminopurine (PMEDAP); and (iii) drugs that do not require any metabolism to inhibit the viral DNA polymerase, i.e. foscarnet (PFA). Drug-resistant virus strains were obtained by serial passage of the OKA strain in human embryonic lung (HEL) fibroblasts and the different drug-resistant mutants were subsequently evaluated for their in vitro susceptibility to a broad range of antiviral drugs. Virus strains emerging under the pressure of ACV, BVDU and BVaraU were cross-resistant to all drugs that depend on the viral TK for activation, but remained susceptible to the acyclic nucleoside phosphonates (i.e. PMEA, PMEDAP and the 3-hydroxy-2-phosphonylmethoxypropyl derivatives of adenine (HPMPA) and cytosine (HPMPC, cidofovir)) and PFA. In contrast, the virus strains selected under pressure of PCV were resistant to PCV, ACV, PMEA and PFA; but not BVDU, BVaraU, GCV, HPMPC or HPMPA. Similar patterns of drug susceptibility were noted for the virus strains selected under the pressure of PMEA or PFA, pointing to an alteration in the viral DNA polymerase as basis for the resistant phenotype selected by PCV, as well as PMEA and PFA. In contrast, the resistant phenotype selected by ACV as well as BVDU and BVaraU may be attributed primarily to mutations in the viral TK gene. Our data thus indicate that ACV and PCV select in vitro for different drug-resistant VZV phenotypes; whether this is also the situation in vivo remains to be investigated.

Topics: 2-Aminopurine; Acyclovir; Adenine; Antiviral Agents; Arabinofuranosyluracil; Bromodeoxyuridine; Cidofovir; Cytosine; DNA-Directed DNA Polymerase; Drug Resistance, Multiple, Viral; Drug Resistance, Viral; Foscarnet; Guanine; Herpesvirus 3, Human; Humans; Microbial Sensitivity Tests; Mutation; Organophosphonates; Phenotype; Selection, Genetic; Thymidine Kinase; Viral Proteins

Topics: Acyclovir; Bromodeoxyuridine; Chemical Phenomena; Chemistry; Ganciclovir; Guanine; Guanosine Triphosphate; Herpesviridae Infections; Humans