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Transplant International : Official... Jun 2010
Topics: Antiviral Agents; Bromodeoxyuridine; Encephalitis, Viral; Herpesvirus 4, Human; Humans; Kidney Transplantation
PubMed: 20070626
DOI: 10.1111/j.1432-2277.2009.01045.x -
British Medical Journal (Clinical... Jun 1981
Review
Topics: Acyclovir; Animals; Antiviral Agents; Bromodeoxyuridine; Genes, Viral; Guanine; Herpes Simplex; Humans; Mice; Recurrence; Simplexvirus; Thymidine Kinase; Virus Replication
PubMed: 6263400
DOI: 10.1136/bmj.282.6279.1821 -
Antimicrobial Agents and Chemotherapy Jan 1998We have evaluated the susceptibility of the murine gamma herpesvirus 68 (MHV-68) to a variety of antiviral agents. The acyclic nucleoside phosphonate analogs cidofovir...
We have evaluated the susceptibility of the murine gamma herpesvirus 68 (MHV-68) to a variety of antiviral agents. The acyclic nucleoside phosphonate analogs cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine], (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (HPMPA), and adefovir [9-(2-phosphonylmethoxyethyl)adenine] efficiently inhibited the replication of the virus in Vero cells (50% effective concentrations [EC50s], 0.008, 0.06, and 2.2 microg/ml, respectively). Acyclovir, ganciclovir, and brivudin [(E)-5-(2-bromovinyl)-2'-deoxyuridine] had equipotent activities (EC50s, 1.5 to 8 microg/ml), whereas foscarnet and penciclovir were less effective (EC50s, 23 and > or =30 microg/ml, respectively). The novel N-7-substituted nucleoside analog S2242 [7-(1,3-dihydroxy-2-propoxymethyl)purine] inhibited MHV-68 replication by 50% at 0.2 microg/ml. The susceptibilities of MHV-68 and Epstein-Barr virus (EBV) to cidofovir, HPMPA, adefovir, and acyclovir were found to be comparable. However, for penciclovir, ganciclovir, brivudin, and S2242, major differences in the sensitivity of MHV-68 and EBV were observed, suggesting that MHV-68 is not always an optimal surrogate for the study of antiviral strategies for EBV. When evaluated with a model for lethal MHV-68 infections in mice with severe combined immunodeficiency, cidofovir proved to be very efficient in protecting against virus-induced mortality (100% survival at 50 days postinfection), whereas acyclovir, brivudin, and adefovir had little or no effect.
Topics: Acyclovir; Animals; Antiviral Agents; Bromodeoxyuridine; Chlorocebus aethiops; Cidofovir; Cytosine; Gammaherpesvirinae; Herpesviridae Infections; Mice; Mice, SCID; Organophosphonates; Organophosphorus Compounds; Vero Cells; Virus Replication
PubMed: 9449280
DOI: 10.1128/AAC.42.1.170 -
Proceedings of the National Academy of... Nov 2008Unlike most DNA viruses, poxviruses replicate in the cytoplasm of host cells. They encode enzymes needed for genome replication and transcription, including their own...
Unlike most DNA viruses, poxviruses replicate in the cytoplasm of host cells. They encode enzymes needed for genome replication and transcription, including their own thymidine and thymidylate kinases. Some herpes viruses encode only 1 enzyme catalyzing both reactions, a peculiarity used for prodrug activation to obtain maximum specificity. We have solved the crystal structures of vaccinia virus thymidylate kinase bound to TDP or brivudin monophosphate. Although the viral and human enzymes have similar sequences (42% identity), they differ in their homodimeric association and active-site geometry. The vaccinia TMP kinase dimer arrangement is orthogonal and not antiparallel as in human enzyme. This different monomer orientation is related to the presence of a canal connecting the edge of the dimer interface to the TMP base binding pocket. Consequently, the pox enzyme accommodates nucleotides with bulkier bases, like brivudin monophosphate and dGMP; these are efficiently phosphorylated and stabilize the enzyme. The brivudin monophosphate-bound structure explains the structural basis for this specificity, opening the way to the rational development of specific antipox agents that may also be suitable for poxvirus TMP kinase gene-based chemotherapy of cancer.
Topics: Amino Acid Sequence; Antiviral Agents; Bromodeoxyuridine; Calorimetry, Differential Scanning; Catalytic Domain; Crystallography, X-Ray; Dimerization; Humans; Models, Molecular; Molecular Sequence Data; Nucleoside-Phosphate Kinase; Protein Structure, Quaternary; Substrate Specificity; Vaccinia virus
PubMed: 18971333
DOI: 10.1073/pnas.0804525105 -
Journal of Dermatological Case Reports Apr 2009Erythema multiforme is a cutaneous reaction that has only rarely been described in varicella zoster virus infection.
BACKGROUND
Erythema multiforme is a cutaneous reaction that has only rarely been described in varicella zoster virus infection.
MAIN OBSERVATIONS
We describe a 76-year old immunocompetent male patient with thoracic herpes zoster. While treated with oral brivudin he developed a widespread cutaneous erythema multiforme. The lesions completely cleared with two weeks with systemic corticosteroids.
CONCLUSION
Varicella zoster infections are possible triggers of erythema multiforme and this is the oldest patient reported with such an association. Brivudin itself has not been reported to induce erythema multiforme and is an unlikely cause of disease in our patient.
PubMed: 21886721
DOI: 10.3315/jdcr.2009.1025 -
Antimicrobial Agents and Chemotherapy Mar 2005The absence of any formally licensed antiadenovirus drugs and the increasing incidence of life-threatening adenovirus infections in immunosuppressed patients warrant the...
The absence of any formally licensed antiadenovirus drugs and the increasing incidence of life-threatening adenovirus infections in immunosuppressed patients warrant the development of effective antiadenovirus compounds. A detailed study was performed on the antiadenovirus activities of several classes of nucleoside and nucleotide analogues in human embryonic lung fibroblast cells. The antiadenovirus activities were evaluated by three methods, viz., evaluating the adenoviral cytopathic effect, monitoring cell viability by a colorimetric assay, and real-time PCR quantitation of viral DNA as a direct parameter for virus replication. The most active and selective compounds were the acyclic nucleoside phosphonate analogues cidofovir, its adenine analogue (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], and the new derivative (S)-2,4-diamino-6-[3-hydroxy-2-(phosphonomethoxy)propoxy]pyrimidine [(S)-HPMPO-DAPy]; the N7-substituted acyclic derivative 2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine (S-2242); and the 2',3'-dideoxynucleoside analogues zalcitabine and alovudine. No antiadenovirus activity was observed for the antiviral drugs ribavirin, foscarnet, acyclovir, penciclovir, and brivudin, while ganciclovir displayed modest activity. However, in human osteosarcoma cells transfected with herpes simplex virus thymidine kinase, ganciclovir demonstrated highly potent antiadenovirus activity, suggesting that the efficacy of ganciclovir against adenovirus is limited by inefficient phosphorylation in adenovirus-infected cells, rather than by insufficient inhibition at the viral DNA polymerase level. Collectively, our antiviral data show that the adenovirus DNA polymerase exhibits sensitivity to a relatively broad spectrum of inhibitors and should be studied further as an antiviral target in antiadenovirus drug development programs.
Topics: Adenoviridae; Antiviral Agents; Ganciclovir; Humans; Nucleosides; Nucleotides; Polymerase Chain Reaction; Thymidine Kinase
PubMed: 15728896
DOI: 10.1128/AAC.49.3.1010-1016.2005 -
Proceedings of the National Academy of... Jun 1979Of a series of five newly synthesized 2'-deoxyuridine derivatives, including 5-vinyl-dUrd, 5-ethynyl-dUrd, 5-(1-chlorovinyl)-dUrd, (E)-5-(2-bromovinyl)-dUrd, and...
Of a series of five newly synthesized 2'-deoxyuridine derivatives, including 5-vinyl-dUrd, 5-ethynyl-dUrd, 5-(1-chlorovinyl)-dUrd, (E)-5-(2-bromovinyl)-dUrd, and (E)-5-(2-iodovinyl)-dUrd, the last two compounds were found to exert a marked inhibitory effect on the replication of herpes simplex virus type 1 [ID50 (mean inhibitory dose), 0.004-0.02 microgram/ml]. Both (E)-5-(2-bromovinyl)-dUrd and (E)-5-(2-iodovinyl)-dUrd were highly selective in their anti-herpes activity in that they did not affect the growth or metabolism of the host (primary rabbit kidney) cells unless drug concentrations were used that were 5,000- to 10,000-fold greater than those required to inhibit virus multiplication. In this sense (E)-5-(2-bromovinyl)-dUrd and (E)-5-(2-iodovinyl)-dUrd proved more selective in their activity against herpes simplex virus type 1 than all other anti-herpes compounds that have been described so far. In animal model systems (namely, cutaneous herpes infections of athymic nude mice), (E)-5-(2-bromovinyl)-dUrd suppressed the development of herpetic skin lesions and mortality therewith associated, whether the compound was administered topically or systemically. Under the same conditions, the standard anti-herpes drug 5-iodo-dUrd (Idoxuridine) offered little, if any, protection. Although the precise mechanism of action of (E)-5-(2-bromovinyl)-dUrd and (E)-5-(2-iodovinyl)-dUrd remains to be established, preliminary findings indicate that they do not specifically act at the thymidylate synthetase step.
Topics: Animals; Antiviral Agents; Bromodeoxyuridine; Mice; Mice, Nude; Simplexvirus; Structure-Activity Relationship; Virus Replication
PubMed: 223163
DOI: 10.1073/pnas.76.6.2947 -
Microbiology and Immunology 1995We compared the selectivity of six anti-varicella-zoster virus (VZV) drugs, which are clinically available or of which clinical efficacy for the treatment of VZV... (Comparative Study)
Comparative Study
We compared the selectivity of six anti-varicella-zoster virus (VZV) drugs, which are clinically available or of which clinical efficacy for the treatment of VZV infections has been reported. Sorivudine (BV-araU) had the most potent anti-VZV effect in the plaque inhibition assay, followed by brivudine (BVDU) and 5-propynyl-arabinofuranosyluracil (Pry-araU). All test compounds, except vidarabine (AraA), had only a very weak effect on human embryonic lung cell growth. The selectivity indexes (ID50 for cell growth/ED50 for VZV plaque inhibition) of BV-araU, BVDU, and Pry-araU were > 1,000,000, 20,000, and > 10,000, respectively, while those of acyclovir and penciclovir ranged from 600 to 800. AraA was much less selective than any of the other drugs tested. We measured the amount of [3H] thymidine incorporated into the acid-insoluble fraction of VZV-infected cells to determine the ability of these drugs to selectively inhibit viral DNA synthesis. [3H]Thymidine incorporation was markedly inhibited by all anti-VZV compounds, except BVDU. Treatment of infected cells with drugs from 32 to 38 hr after infection inhibited the DNA synthesis to the same extent as VZV plaque formation, except that AraA inhibited the DNA synthesis at a lower dose than for VZV plaque formation. DNA synthesis in non-infected growing cells was inhibited to the same extent as cell growth. A particularly high selectivity index for the inhibition of DNA synthesis was noted for BV-araU, which was defined as the ratio of inhibitions of DNA synthesis in VZV-infected and non-infected. The highest selectivity indexes were recorded for BV-araU > Pry-araU > acyclovir > or = penciclovir > AraA.
Topics: Antiviral Agents; Cell Division; Cell Line; Cells, Cultured; DNA; DNA Replication; DNA, Viral; Herpesvirus 3, Human; Humans; Lung; Nucleosides; Structure-Activity Relationship; Thymidine; Viral Plaque Assay
PubMed: 7603364
DOI: 10.1111/j.1348-0421.1995.tb02189.x -
Antiviral Chemistry & Chemotherapy Sep 2001We report the design, synthesis and antiviral evaluation of a number of lipophilic, masked phosphoramidate derivatives of the antiherpetic agent...
We report the design, synthesis and antiviral evaluation of a number of lipophilic, masked phosphoramidate derivatives of the antiherpetic agent (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), designed to act as membrane soluble prodrugs of the free nucleotide. The phosphoramidate derivatives of BVDU that contain L-alanine exhibited potent anti herpes simplex virus type 1 and varicella-zoster virus activity but lost marked activity against thymidine kinase-deficient virus strains. The phosphoramidate derivative bearing the amino acid alpha,alpha-dimethylglycine showed poor activity in all cell lines tested. It appears that successful kinase bypass by phosphoramidates is highly dependent on the nucleoside analogue, amino acid and ester structure, as well as the cell line to which the drugs are exposed.
Topics: Acyclovir; Amides; Antiviral Agents; Bromodeoxyuridine; Cell Line; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Viral; Fibroblasts; Herpesvirus 3, Human; Humans; Lung; Molecular Structure; Phosphoric Acids; Simplexvirus; Structure-Activity Relationship; Vaccinia virus; Vesicular stomatitis Indiana virus
PubMed: 11900348
DOI: 10.1177/095632020101200504 -
Japanese Journal of Infectious Diseases Nov 2020Morphological changes in the structure of the herpes simplex virus 1 (HSV-1) viral thymidine kinase (vTK) polypeptide usually lead to conferring acyclovir (ACV)...
Morphological changes in the structure of the herpes simplex virus 1 (HSV-1) viral thymidine kinase (vTK) polypeptide usually lead to conferring acyclovir (ACV) resistance. HSV-1 I4-2, in which a UAG stop codon is present at the 8th position between the 1st initiation AUG codon (1st position) and the 2nd initiation AUG codon (46th position) of the HSV-1 vTK gene, showed sensitivity to ACV. In contrast, HSV-1 KG111, in which a UAG stop codon was artificially inserted at the 44th position, showed resistance to ACV at 39˚C. The mechanism underlying the difference in the sensitivity profiles was elucidated. The virus recombinants HSV-1-TK(8UAG) and HSV-1-TK(44UAG) containing a UAG stop codon at the 8th and 44th positions counted from the 1st initiation codon, respectively, were generated and tested for susceptibility to antiviral compounds. HSV-1-TK(8UAG) and HSV-1-TK(44UAG) were sensitive and resistant to ACV and BVdU at 37˚C, respectively. The expression level of the truncated vTK translated from the 2nd initiation codon in Vero cells infected with HSV-1-TK(44UAG) was clearly less than that with HSV-1-TK(8UAG) in a temperature-dependent manner. The differences in the antiviral sensitivity profiles were due to the position of the UAG stop codon between the 1st and the 2nd initiation codons.
Topics: Acyclovir; Animals; Antiviral Agents; Bromodeoxyuridine; Cell Line; Chlorocebus aethiops; Codon, Initiator; Codon, Terminator; Drug Resistance, Viral; Herpesvirus 1, Human; Humans; Microbial Sensitivity Tests; Mutation; Thymidine Kinase; Vero Cells; Viral Plaque Assay; Virus Replication
PubMed: 32611982
DOI: 10.7883/yoken.JJID.2020.313