Showing papers in "Antiviral Chemistry & Chemotherapy in 1992"
TL;DR: Eighteen amino acid esters of the antiherpetic drug, acyclovir, were synthesized as potential prodrugs for oral administration and the L-valyl ester, 256U87, was the best prodrug.
Abstract: Summary Eighteen amino acid esters of the antiherpetic drug, acyclovir, were synthesized as potential prodrugs for oral administration. The esters were examined for in vitro antiviral activity against herpes simplex virus Type 1 (HSV-1). They were found to have less potency than the parent compound. Their efficiencies as pro drugs were evaluated in rats by measuring the urinary recovery of acyclovir. Ten prodrugs produced greater amounts of the parent drug in the urine. The L-amino acid esters were better prodrugsthan the correspond ing D- or D,L-isomers, suggesting the involvement of a stereoselectivetransporter. The L-valyl ester, 256U87, was the best prodrug. Sixty three per cent of its administered dose was excreted as acyclovir in the urine, a considerable improvement over acyclovir itself, for which this value was 19%. Since 256U87 was stable in aqueoussolutions, its conversion to acyclovir in vivo was probably enzyme catalyzed. This L-valyl ester prodrug of acyclovir is now undergoing clinical evaluation.
244 citations
TL;DR: The antiviral effects of 7,7a-diepialexine correlated with the inhibitory activity against purified pig kidney α-glucosidase 1 of the glycop Protein processing enzymes and the reduced cleavage of the precursor HIV-1 glycoprotein gp160.
Abstract: Alexine, a naturally occurring pyrrolizidine alkaloid, isolated from Alexa leiopetala, and four stereoisomers, isolated from Castanospermum australe, were investigated for inhibitory activity against the growth of HIV-1. Only treatment with the 7,7a-diepialexine restricted virus growth (IC 50 0.38 mM) although it was less active than the indolizidine alkaloid castanospermine (IC 50 0.02 mM). The antiviral effects of 7,7a-diepialexine, like castanospermine, correlated with the inhibitory activity against purified pig kidney α-glucosidase 1 of the glycoprotein processing enzymes and the reduced cleavage of the precursor HIV-1 glycoprotein gp160
50 citations
TL;DR: Only in the brain and testes were drug levels less than in plasma, although effective antiviral concentrations of zidovudine were achieved in brain and CSF, and rapid and extensive absorption and considerable penetration into tissues were observed for all species studied.
Abstract: Summary Preclinical and clinical studies on the disposition of zidovudine, a thymidine analogue with potent activity against human immunodeficiency virus, identified significant species differe.nces in the metabolism and elimination of the drug. Zidovudine was extensively metabolized to the 5'-O~glucuronide in man and other primates. Rabbits and dogs were intermediate in their extent of biotransformation to the glucuronide conju gate, whereas rats and mice excreted the drug largely unchanged. Decreased metabolism was compen sated by increased renal elimination, such that plasma elimination phase half-lives for zidovudine were simi lar (0.6-1.1 h) in all species. Rapid and extensive absorption and considerable penetration into tissues were also observed for all species studied. Only in the brain and testes were drug levels less than in plasma, although effective antiviral concentrations of zidovu dine were achieved in brain and CSF. This review summarizes the variety of studies of the absorption, distribution, metabolism, and elimination of zidovu dine in several species, including humans.
47 citations
TL;DR: Three novel compounds, namely, phenoxan, phenalamide A1, and thiangazole, were found to suppress HIV-1 replication in cell cultures, and like HEPT, TIBO and TIBO derivatives they are highly specific since they could not interfere with HIV-2ben dependent MT-4 cell death.
Abstract: Three novel compounds, namely, phenoxan, phenalamide A1, and thiangazole, were found to suppress HIV-1 replication in cell cultures. The compounds were discovered by screening crude extracts from myxobacteria and were isolated from two strains of Polyangium sp. and a strain of Myxococcus stipitatus. Their structures have been elucidated. The cytotoxic concentrations for MT-4 cells were 6.6 μM for phenoxan, 102 μM for phenalamide A1, and 4.7 μM for thiangazole. Phenoxan inhibited the HIV-1-dependent cell death at concentrations of as low as 6.6 nM. Phenalamide A1 could prevent the HIV-1 infection of MT-4 cells even at concentrations of 1.02nM, and thiangazole at 4.7 pM. In our assay thiangazole is at least 100 times more active than AZT. The compounds could not prevent syncythia formation induced by HIV-1. However, like HEPT (Baba et al., 1989; Miyasaka et al., 1989) and TIBO (Pauwels et al., 1990) derivatives they are highly specific since they could not interfere with HIV-2ben dependent MT-4 cell death. ...
42 citations
TL;DR: An understanding of the relationship between the structure of porphyrins and their antiviral effects is expected to lead to the design of additional derivatives with more potent antiviral activity and to unravelling of molecular details involved in the association between the V3 loop of gp120 and antiviral compounds targeted to this loop.
Abstract: Recent observations that haernin inhibited the replication of the human immunodeficiency virus (HIV-1) and the reaction between the HIV-1 envelope glycoprotein gp120 and antibodies specific for the V3 hypervariable loop of this glycoprotein were an enticement to determine whether or not additional porphyrins had similar activities. Several porphyrin derivatives, particularly meso-tetra (4-carboxyphenyl) porphine, were more potent inhibitors of HIV-1 replication than haernin. They blocked the binding of homologous antibodies to synthetic peptides corresponding to V3 hypervariable loops of 21 distinct HIV-1 isolates, and inhibited the replication in lymphocytic (MT-2) and promonocyte (U937) cell lines of several HIV-1 isolates, tested (IIIB, RF, SF-2, and MN). Compounds with inhibitory activity had a tetrapyrrole ring and, carboxyl or sulphonate groups. However, antiviral activity depended on minor structural difference's between distinct derivatives endowed with these two features. Metalloporphyrins had a ...
38 citations
TL;DR: Polyhydroxycarboxylates derived from phenolic (PDP) compounds were found to be selective inhibitors of human cytomegalovirus (CMV), herpes simplex virus type 1, type 2, HSV-2, thymidine kinase-deficient HSV and vaccinia virus replication at concentrations that are not toxic to the host cells.
Abstract: Polyhydroxycarboxylates (MW 3800–14000) derived from phenolic (PDP) compounds were found to be selective inhibitors of human cytomegalovirus (CMV), herpes simplex virus type 1 (HSV-1), type 2 (HSV-2), thymidine kinase-deficient (TK−) HSV-1 and vaccinia virus replication at concentrations that are not toxic to the host cells. The PDP compounds were not inhibitory to parainfluenza virus, reovirus, Sindbis virus, or Semliki forest virus. The polycarboxylate aurintricarboxylic acid (ATA) (MW 1149–3336) also proved inhibitory to CMV and HSV replication. The anti-CMV and anti-HSV activities of the ATA polymers increased with increasing molecular weight. The mechanism of anti-CMV activity of both the PDP and ATA series of compounds can be attributed to the inhibition of virion attachment to the cells, probably due to an interaction of these polyanionic compounds with the positively charged domains of the viral envelope glycoproteins.
37 citations
TL;DR: A series of 5-alkynyl substituted 2-deoxyuridine and β-D-arabinofuranosyluracil nucleosides were synthesized and evaluated for in vitro activity against varicella-zoster virus (VZV) as discussed by the authors.
Abstract: A series of 5-alkynyl substituted 2′-deoxyuridine and β-D-arabinofuranosyluracil nucleosides were synthesized and evaluated for in vitro activity against varicella-zoster virus (VZV). Three promising analogues, 1-(β-D-arabinofuranosyl)-5-ethynyluracil (EYaraU), 2′-deoxy-5-prop-1-ynyluridine (PYdU) and 1-(β-D-arabinof uranosyl)-5-prop-1-ynyluracil (PYaraU) had potent activity against eight strains of VZV with IC50 values averaging 1 μM. This activity was selective for VZV as the compounds were significantly less active against herpes simplex viruses (HSV) and human cytomegalovirus (HCMV) in contrast to 2′-deoxy-5-ethynyluridine (EYdU) which is highly active against all three viruses. The ability of these compounds to inhibit the growth of Vera or MRC-5 cells was over 2 orders of magnitude less than their antiviral activity (CC50 in Vero cells 350 μM for EYaraU and >500 μM for PYdU and PYaraU and >500 μM for all 3 compounds in MRC-5 cells). Direct comparative studies showed these compounds to be more potent...
35 citations
TL;DR: The inhibitory effect of suramin and ATA on syncytium formation was independent of the virus strain or cell type, but for dextran sulphate and pentosan polysulphate, it was dependent on virus strain, and for heparin, castanospermine, and sCD4, it is dependent on both the virus strains and cell type.
Abstract: Polyanionic compounds [i.e. pentosan polysulphate, dextran sulphate, heparin, suramin, and aurintricarboxylic acid (ATA)] and castanospermine were examined for their inhibitory effect on human immunodeficiency virus (HIV) strains (HIV-1IIIB, HIV-1RF, HIV-2ROD and HIV-2EHO) in two different assays (HIV cytopathicity in MT-4 cells and HIV antigen expression in CEM cells). In the MT-4 assay dextran sulphate and pentosan polysulphate were more active against HIV-2ROD, suramin was more active against HIV-1RF, and ATA more active against HIV-2EHO-Heparin was less, but castanospermine was more, active against the two HIV-2 strains. In the CEM assay dextran sulphate and suramin were equally active against all HIV strains, pentosan polysulphate was more active against both HIV-2 strains, whereas heparin was less active against HIV-2ROD and ATA again was more active against HIV-2EHO. The compounds and soluble CD4 (sCD4) were also tested in the HIV-induced syncytium formation assay, where chronically infected HUT-78...
29 citations
TL;DR: Well characterized AZT-resistant virus was modestly cross-resistant to compounds 2b and 2d, and the most potent compound was 1-(ethoxymethyl)-6-(phenylselenenyl)-5-ethyluracil 2d with a median effective concentration of 17 nM in primary human lymphocytes and no discernable cytotoxicity in these cells or rapidly dividing CEM and Vero cells.
Abstract: The reaction of chloromethyl ethyl ether with bis(trimethylsilyl)uracil derivatives yield 1-(ethoxymethyl)pyrimidines 1 a-d in good yield. Lithiation of 1 a-d with lithium diisopropylamide at -78°C, followed by reaction with diphenyl diselenide as an electrophile, gave 1-(ethoxymethyl)-6-(phenylselenenyl)uracils 2a-d in 70-80% yield. The 6-phenylselenenyl acyclic pyrimidines 2b and 2d exhibited selective in vitro activity against HIV-1 and HIV-2 in primary human lymphocytes
28 citations
TL;DR: The integration protein of the human immunodeficiency virus type 1 was purified from recombinant bacteria overproducing this enzyme, yielded a homogeneous protein preparation showing specific DNA cutting and joining activities and was used to test selected compounds for their inhibitory potential against integrase.
Abstract: The integration protein of the human immunodeficiency virus type 1 was purified from recombinant bacteria overproducing this enzyme. The final step of purification, namely chromatography on polyUsepharose, yielded a homogeneous protein preparation showing specific DNA cutting and joining activities. For a convenient assay of the endonuclease reaction, a 21-mer duplex oligonucleotide corresponding to the U5-LTR end of the viral DNA was radiolabeled at the dinucleotide that is removed by the enzyme. After the reaction, assay mixtures were passed through DEAE-cellulose filters which bind the substrate, but not the short radiolabeled product. Thus, an enzyme-dependent decrease of bound radioactivity was observed with time. Reaction rate was linearly dependent on enzyme concentration and the amount of substrate used was far below saturating concentrations. The reaction showed a pH-optimum at 7.5 and was strictly dependent on the presence of Mn2+. The presence of reducing agents like 2-mercaptoethanol was not e...
27 citations
TL;DR: The antiviral activity of certain porphyrins has been demonstrated in the absence of light, suggesting a non-photochemical process.
Abstract: A series of amino- and hydroxytetraphenylporphyrin derivatives was found to have activity against the human immunodeficiency virus type 1 (HIV-1) in human peripheral blood mononuclear cells. Activi...
TL;DR: A number of zidovudine phosphoramidate and phosphorodiamidate derivatives were prepared, including some previously unreported benzyl esterified amino acyl compounds, which were found to be active in vitro against the human immunodeficiency virus and tested subsequently in the S+L-tissue culture assay against urethane leukaemia virus (ULV), a murine leukaemic virus (MuLV).
Abstract: Summary A number of zidovudine phosphoramidate and phos phorodiamidate derivatives were prepared, including some previously unreported benzyl esterified amino acyl compounds. These werefound to be active in vitro against the human immunodeficiency virus (HIV-1), and were tested subsequently in the S+L-tissue culture assay against urethane leukaemia virus (ULV), a murine leukaemia virus (MuLV). The fifteen com pounds tested showed a similar range of activity against the two viruses. No active compounds were missed in the MuLV system which was usually more sensitive to antiviral effects. Five compounds showed sometoxicity tothe mousecells only. We are using this system in parallel with HIV assays to identify those derivatives Which will be tested subsequently against a murine retrovirus in vivo.
TL;DR: It is found that several dye compounds have the ability to inhibit the binding of HIV rgpl 20 to the Leu3a epitope of CD4 on PBL and one of these compounds can inhibit the growth of HIV In vitro.
Abstract: We have found that several dye compounds have the ability to inhibit the binding of HIV rgp 120 to the Leu3A epitope of CD4 on PBL. One of these compounds, selected for further testing as the best candidate, can inhibit the growth of HIV in vitro. The tested dyes have varying degrees of specificity and efficacy in inhibiting the binding of rgp 120. These results may point towards compounds that can be useful therapeutics against HIV
TL;DR: A new polyacetal polysulphate was synthesized starting from dextran through oxidation, reduction, and subsequent sulphation that inhibited HIV-1- and HIV-2-induced cytopathicity in MT-4 cells and generated low titres of an antiviral principle that was at least partially interferon-like.
Abstract: A new polyacetal polysulphate, termed PAPS, was synthesized starting from dextran through oxidation, reduction, and subsequent sulphation. PAPS inhibited HIV-1- and HIV-2-induced cytopathicity in MT-4 cells at concentrations comparable to those required for dextran sulphate (MW5000) to inhibit the cytopathicity of these viruses (50% inhibitory concentration: 0.4–0.04 μg ml−1). At these concentrations PAPS had no anticoagulant activity. PAPS suppressed syncytium formation between MOLT-4 cells and persistently HIV-1- or HIV-2-infected HUT-78 cells at a concentration of 1 μg ml−1, that is 25- to 30-fold lower than that required for dextran sulphate to inhibit syncytium formation. Like dextran sulphate, PAPS inhibited HIV-1 binding to the cells and anti-gp120 mAb binding to HIV-1 gp120. Also, PAPS proved equally active as dextran sulphate against herpes simplex virus, cytomegalovirus and the arenaviruses Junin and Tacaribe, and 10-fold more active than dextran sulphate against vaccinia, Sindbis, influenza A, ...
TL;DR: Drugs, based on peptides that mimic the protein-protein interactions required for virus assembly, may have therapeutic potential because they competitively inhibit attachment of the glycoprotein to intracellular virus structures during assembly of the virion.
Abstract: Summary Peptides, corresponding to amino acid sequences in the cytoplasmic domains of the transmembranal glycoproteins encoded by Sindbis and vesicular sto matitis viruses, inhibited release of virus particles and infectious virus when added to infected cells for a 2 h period during a one-cycle growth curve. Each inhibi tory peptide was specific for its intended virus. The shortest peptide with antiviral activityfor Sindbis virus contained six amino acids, and a related peptide that was acylated at the amino terminus with octanoic acid was ten-fold more potent as an inhibitor. Neither of these peptides affected the synthesis of viral structu ral proteins, but a third peptide inhibited proteolytic processing of the Sindbis virus E2 glycoprotein. Inhi bition of vesicular stomatitis virus particle release was dose-dependent in the range of 50-400 f.Lg mr ' for a peptide corresponding to the G glycoprotein cytoplas mic domain. We postulate that these peptides compe titively inhibit attachment of the glycoprotein to intracellular virus structures during assembly of the virion. Thus, drugs, based on peptides that mimic the protein-protein interactions required for virus assem bly, may have therapeutic potential.
TL;DR: Among thirteen newly synthesized pyridobenzoazole derivatives which have been examined for anti-myxovirus and antiherpesvirus activities, three benzimidazoles emerged as potent anti-orthomyxo- or paramyxovirus compounds.
Abstract: Among thirteen newly synthesized pyridobenzoazole derivatives which have been examined for anti-myxovirus and antiherpesvirus activities, three benzimidazoles emerged as potent anti-orthomyxo- or paramyxovirus compounds. 4-Cyano-2-benzamide-1-oxo-1,5-dihydropyrido[1,2a]benzimidazole (CBO-PB) showed broad antiviral activities against paramyxo-and orthomyxoviruses with EC50 of 0.1–2.0 μg ml−1, and 2-cyano-1-amino derivatives of CBO-PB (CCI-PB) were inhibitory to paramyxoviruses at 1.4–8.5 (μg ml−1 by a plaque reduction method. The third compound, 2-ethoxycarbonyl derivatives of CCI-PB was inhibitory only to respiratory syncytial virus (RSV) at 15–28 μg ml−1. Selectivity indexes of these 3 compounds for RSV in HeLa cells were 60, 86, and >13, respectively. All three compounds inhibited syncytium formation of RSV and Parainfluenzavirus (PFLUV) type 3 at comparable concentrations with EC50 for plaque formation. They inhibited antigen production of RSV and PFLUV at the concentrations that were 4 to 20-fold high...
TL;DR: Oral administered PCV was less effective than ganciclovir (GCV) in reducing mortality of infected mice, but was of similar effectivenss to acyclovir (ACV).
Abstract: Mice inoculated intranasally with a potentially lethal dose of HSV-1 (strain SC16) were used to evaluate the efficacy of penciclovir (PCV) and its oral form, famciclovir (FCV) in the treatmentof acute herpes encephalitis. In a comparative experiment, orally administered PCV was less effective than ganciclovir (GCV) in' reducing mortality of infected mice, but was of similar effectivenss to acyclovir (ACV). Late deaths from ongoing infections were observed following cessation of treatment with both ACV and FCV. Delaying the onset of treatment by more than 1 day post infection markedly reduced the ability of orally administered ACV, PCV, and FCV to prevent death. Treatment from day 1 with FCV administered ad libitum in the drinking water resulted in rapid clearance of infectious virus from all parts of the brain, but latent viruswas detected by Southern blot hybridization in the peripheral and central nervous system of survivors 1 month post infection. In untreated mice, infectious virus was also detected in the epithelium of the turbinate bones and in the lungsfrom 1day after intranasal inoculation, and acute inflammatory changes were seen in the lungs. FCV was more effective inclearing virusfrom the lungs than from the turbinate bones in these mice. These data, concerning the importance of virus replication in the respiratory tract with regard to subsequent encephalitis, are considered to be a novel aspect of this study.
TL;DR: When the amount of virus was reduced to 100 infectious doses or less, treatment with FLT resulted in a significant delay in the appearance of viral antigen, and at an inoculum of 2–10 infectious doses per monkey, FLT treatment showed a prophylactic effect.
Abstract: Inoculation of cynomolgus monkeys with simian immunodeficiency virus (SIVSM) results in an acute infection with circulating viral antigen. The time for appearance of the viral antigen peak was dependent on the dose of virus given, a reduced dose of virus resulting in a later peak. 3′-Fluorothymidine (FLT) was given at a dose of 3 × 5mg kg−1 day−1 starting 8 h before virus inoculation and then every 8 h for 10 days. In monkeys inoculated with 500–2500 infectious doses of SIVSM no significant effect of treatment with FLT was seen. When the amount of virus was reduced to 100 infectious doses or less, treatment with FLT resulted in a significant delay in the appearance of viral antigen. At an inoculum of 2–10 infectious doses per monkey, FLT treatment showed a prophylactic effect.
TL;DR: Among the substituted isoflavans and isoflavenes tested so far, the intermediate compound 6-chloro-3 (2H)-is oflavene-4′-carboxylic acid (XIX) was unexpectedly the most potent inhibitor of rhinovirus 1B plaque formation.
Abstract: Oxazolinyl-isoflavans and −3(2H)-isoflavenes, substituted or not with a chlorine atom, were synthesized in order to compare their anti-rhinovirus activity with that of previously studied analogous compounds.The activity of the oxazolines and of the esters and acids, which are intermediates in the synthesis, was studied in vitro against rhinovirus serotype 1B infection in HeLa cells. The ability of various non cytotoxic concentrations to interfere with the development of the viral cytopathic effect and plaque formation was examined.All the tested compounds exerted a significant antiviral activity, and most of them were as active as some representative compounds of the oxazolinyl-phenoxyalkylisoxazole (WIN) series. 6-Oxazolinylisoflavan (VI) appeared to be the most interesting compound due to its high activity and therapeutic index. Among the substituted isoflavans and isoflavenes tested so far, the intermediate compound 6-chloro-3 (2H)-isoflavene-4′-carboxylic acid (XIX) was unexpectedly the most potent in...
TL;DR: Novel phosphate triester derivatives of the antiviral drug araA and the anti-leukaemic agent araC have been prepared as membrane-soluble pro-drugs of the bio-active free nucleotides, and it is notable that the trichloroethyl derivative is most active in each case.
Abstract: Novel phosphate triester derivatives of the antiviral drug araA and the anti-leukaemic agent araC have been prepared as membrane-soluble pro-drugs of the bio-active free nucleotides. In particular, novel trichloro- and trifluoroethyl phosphates have been prepared using phosphorochloridate chemistry, and are fully characterized. An in vitro assay indicates inhibition, by each of the compounds, of thymidine incor-portion by mammalian epithelial cells. It is notable that the trichloroethyl derivative is most active in each case, and in the case of araC its activity appears to exceed that of the parent nucleoside.
TL;DR: Although significant enhancements in systemic availability were observed with some of the 5′-esters of this series, their limited water solubility precluded their use in intravenous formulations, and no clear relationship between systemic availability and Solubility, partition coefficient, or stability was observed.
Abstract: 6-Methoxypurine arabinoside [9-(β-D-arabinofuranosyl)-6-methoxy-9H-purine; 1] is a potent and selective agent against varicella-zoster virus in vitro. Studies in the rat indicated that extensive first pass metabolism of this nucleoside occurred after oral dosing, presumably from high levels of adenosine deaminase in the intestine. Only 3.8% of an oral dose of 6-methoxypurine arabinoside was recovered in the urine. In an attempt to improve these unfavourable pharmacokinetics, a series of twenty-five 2′-esters of 6-methoxypurine arabinoside were prepared either by direct acylation or by a protection, acylation, and deprotection sequence. These esters were evaluated in the rat for their suitability as prodrugs on the basis of urinary recovery of 1 after oral dosing. The straight-chain aliphatic esters, but not the branched chain or aromatic esters, improved this urinary recovery. The 2′-valerate, hexanoate, heptanoate, and octanoate esters (2d–g, respectively) were the most effective, with urinary recoveries...
TL;DR: It is suggested that human lymphoblastoid interferon can control the disease activity and eliminate hepatitis C virus from patients with chronic hepatitis C.
Abstract: Thirty-two patients with chronic hepatitis who were positive for hepatitis C virus (HCV) RNA by polymerase chain reaction and had antibody to HCV (anti-HCV), were enrolled in this study. Twenty of them were also positive for antibody to the GOR epitope (anti-GOR). Sixteen of the enrolled patients were treated with human lymphoblastoid interferon for six months. Treatment was initiated with 3 million units of interferon daily for 2 weeks, followed by 3 million units three times a week for 6 weeks and 1.5 million units three times a week for 16 weeks. The efficacy of therapy was assessed by comparison with the results in 16 untreated patients. Aminotransferase values, titre of anti-HCV and anti-GOR antibodies showed significant decreases throughout the therapy compared with baseline levels and the untreated patients. After a 3 month follow-up, nine treated patients (56.3%) had normal aminotransferase activities and six of them eliminated HCV RNA from their sera (37.5%). Three of these six patients became ne...
TL;DR: Novel antiviral antibiotic quartromicins A1 and D1 significantly inhibited human immunodeficiency virus (HIV)-induced cytopathic effect and virus specific antigen expression at concentrations of 25–100 μg ml−1 in MT-4 cells infected with HTLV-IIIB.
Abstract: Novel antiviral antibiotic quartromicins A1 and D1, isolated from Amycolatopsis orientalis, significantly inhibited human immunodeficiency virus (HIV)-induced cytopathic effect and virus specific a...
TL;DR: A novel reverse transcriptase (RT) assay based on the combined use of macrobead-bound template and 125I-iododeoxyuridine-triphosphate was used to determine the IC50 values of various RT inhibitors, showing that, in contrast to different nucleic acids and oligonucleotides, the classic RT inhibitors either did not interfere or only interfered weakly with the binding of RT to the carrier bound template-primer, template, or primer.
Abstract: A novel reverse transcriptase (RT) assay based on the combined use of macrobead-bound template and 125I-iododeoxyuridine-triphosphate (IUTP) was used to determine the IC50 values of various RT inhibitors. The results showed that this assay and the conventional assay gave similar IC50 values. The introduction of carrier bound template-primer, template, or primer also made it possible to design assays revealing the mechanism of action of various RT inhibitors. Unlabelled inhibitor substance could be incubated with carrier bound template-primer in the presence of excess enzyme, after which the inhibitor was removed and the residual template-primer function was analysed by RT assay. By this procedure it was found that chain elongation terminators like 2′,3′-dideoxy-TTP and 3′-azido-TTP destroyed the template-primer at low concentrations which corresponded to the amount of primer. In contrast, 20–200 times higher concentrations were needed for template-primer destruction when using substances continuously inco...
TL;DR: The in vitro antiviral activity of ribavirin (Rby; 1-β-D-ribof uranosyl-1,2,4-triazole-3-carboxamide) against selected members of the Picornaviridae is described and prophylactic administration of Rbv significantly improved virus yield reduction, especially in Polio-1.
Abstract: The in vitro antiviral activity of ribavirin (Rbv; 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) against selected members of the Picornaviridae is described. When antiviral activity was determined by reduction of infectious virus progeny, Rbv was active against human rhinovirus type 2 (HRV-2) and poliovirus type 1 (Polio-1) in both a drug concentration and multiplicity of infection-(MOI) dependent response. However, an antiviral activity rating assay based on the reductions of cellular cytopathic effects (CPE) indicated that Rbv was active against human rhinoviruses, but was less active against polioviruses
TL;DR: Results of this study suggest that the antiviral effect of PFA involves an immediate and direct mechanism targeted at cell-free virus and that long-term continuous intravenous infusion of P FA has significant anti-retroviral activity in vivo.
Abstract: Phosphonoformate (PFA) is a simple pyrophosphate analogue which is a topical and parenteral treatment for human herpes virus infections and is currently undergoing evaluation for treatment of human immunodeficiency virus (HIV) and cytomegalovirus infections associated with (AIDS). In this study, antiretroviral activity of PFA was demonstrated by two separate treatment regimens. In the first, an inoculum of feline leukaemia virus (FeLV) in plasma from viraemic cats was treated with 1024 μM PFA prior to intravenous inoculation into susceptible animals. Three of four cats given the PFA treated inoculum were protected from viraemia by the PFA treatment, while 2 of 2 challenge controls receiving sham treated inoculum and 6 of 6 untreated challenge controls became viraemic. In the second regimen, a long-term continuous intravenous infusion of PFA (1000 mg kg−1 day−1) was administered to 6 young cats beginning 1–2 days prior to and extending 4 weeks following intravenous inoculation with FeLV. Five of the six PF...
TL;DR: HTLV-I and II, along with simian T-lymphotropic virus (STLV) and bovine leukaemia virus (BLV), form a phylogenetic group which is distinct from ungulate, non-human primate and human lentiviruses such as visna, simian immunodeficiency virus (SIV), and human immunodficiency viruses types 1 and 2.
Abstract: The human T-cell lymphotropic viruses types I and II (HTLV-I, II) pose challenges to researchers and clinicians who seek to unveil mechanisms of viral transformation and pathogenesis. HTLV-I infection in humans is associated with a wide array of primary and secondary diseases ranging from mild immunosuppression to adult T-cell leukaemia/lymphoma and HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a neurological degenerative syndrome. As retroviruses, HTLV-I and II share similar replicative cycles with human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome. However, in contrast to HIV-I which destroys CD4+T cells HTLV-I and II can preferebtially transform a CD4+T-cell subset to an unrestricted growth state
TL;DR: This paper, which is published in two parts, reviews the literature pertaining to antiviral chemotherapy of viruses of veterinary importance, and includes the feline virus diseases, in dogs, horses, cattle, pigs, birds, and fish.
Abstract: This paper, which is published in two parts, reviews the literature pertaining to antiviral chemotherapy of viruses of veterinary importance. While early reports in the 1970s referred to the chemot...
TL;DR: It is found that combinations of these two agents synergistically inhibited HIV replication in human peripheral blood leucocytes (PBL).
Abstract: Interferon alpha, either leukocyte derived or the recombinant form, and the DNA gyrase inhibitor coumermycin A1 both inhibited human immunodeficiency virus type 1 (HIV) replication in vitro. We hav...
TL;DR: H9 cells were shown to be much more sensitive to the effects of the analogues upon deoxynucleoside triphosphate pools than CEM cells were, and the synergistic combination of 3′-azido-3′-deoxythymidine and 3′
Abstract: A combination of 3′-azido-3′-deoxythymidine (AZT) with 3′-fluoro-3′-deoxythymidine (FLT) has been shown previously to give synergistic inhibition of human immunodeficiency virus replication and greatly reduced cytotoxicity in vitro. The phosphorylation of the compounds, and their effect upon the natural deoxynucleoside triphosphate pools, were compared in CEM, H9, and HIV-infected H9 lymphoblastoid cells, both for the compounds when used alone and when combined together.Higher levels of FLT triphosphate than AZT triphosphate, and higher levels of AZT monophosphate than FLT monosphosphate, were formed in all cell types. Both compounds were phosphorylated most efficiently in CEM cells, whereas they were least efficiently phosphorylated in infected H9 cells.Owing to competition, the phosphorylation of both analogues was reduced when used in combination, compared to the phosphorylation of the separate compounds. The phosphorylation of the separate compounds was therefore at a maximum and was not increased by ...