In this work, we investigated the anti-hepatitis B virus (HBV) activity of lamivudine, adefovir, tenofovir, penciclovir and lobucavir after short-term (i.e. 24 or 48 h) or continuous (9 days) exposure of the HBV-containing cell line, HepG2 2.2.15, to these drugs. Lamivudine maintained significant anti-HBV activity when added for only 24 or 48 h to the cell cultures compared to when the drug was present for the whole period (9 days) on the cells, i.e. 50% effective concentration (EC50) values for the inhibition of HBV DNA synthesis were 0.07 +/- 0.02 microgram ml-1 after 24 h of incubation, 0.02 +/- 0.01 microgram ml(-1) after 48 h of incubation and 0.0016 +/- 0.001 microgram ml(-1) after 9 days of incubation. Similarly, the nucleoside phosphonate analogues, adefovir and tenofovir, retained significant anti-HBV activity when added for only a short period of time to the cells. The EC50 values were 12 +/- 1 microgram ml(-1) (24 h) and 1.0 +/- 0.2 microgram ml(-1) (48 h) vs 0.003 +/- 0.001 microgram ml(-1) (9 days) for adefovir, and 6.5 +/- 1.1 microgram ml(-1) (24 h) and 0.8 +/- 0.1 microgram ml(-1) (48 h) vs 0.03 +/- 0.02 microgram ml(-1) (9 days) for tenofovir. In contrast, penciclovir and lobucavir lost most of their anti-viral activity when present on the cells for 48 h or less.
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The early effectiveness of combinatorial antiretroviral therapy (cART) in the treatment of HIV infection has been compromised to some extent by rapid development of multidrug-resistant HIV strains, poor bioavailability, and cumulative toxicities, and so there is a need for alternative strategies of antiretroviral drug discovery and additional therapeutic agents with novel action modes or targets. From this perspective, we first review current strategies of antiretroviral drug discovery and optimization, with the aid of selected examples from the recent literature. We highlight the development of phosphate ester-based prodrugs as a means to improve the aqueous solubility of HIV inhibitors, and the introduction of the substrate envelope hypothesis as a new approach for overcoming HIV drug resistance. Finally, we discuss future directions for research, including opportunities for exploitation of novel antiretroviral targets, and the strategy of activation of latent HIV reservoirs as a means to eradicate the virus.
We have previously shown that the N-7 substituted acyclic nucleoside analog 2-amino-7-[1,3-dihydroxy-2-propoxy)methyl]purine (compound S2242) is, both in vitro and in animal models, a potent inhibitor of the replication of several herpesviruses (Neyts et al., Antimicrob. Agents Chemother. 39:56-60, 1995). Here we report on the potent and selective antiviral activity of S2242 against vaccinia virus (VV), an orthopoxvirus. The 50% effective concentrations for inhibition of VV-induced cytopathic effect and viral DNA synthesis in cell culture were 2.4 and 0.2 microg/ml, respectively. We next studied the efficacy of S2242 in VV-infected mice. Immunocompetent NMRI mice that had been inoculated intravenously with VV developed tail lesions. Mice that had been treated for 5 consecutive days via the subcutaneous (s.c.) route with 100 mg of the diacetate ester prodrug of S2242 (compound H961) per kg of body weight did not develop any lesions and demonstrated no adverse effects. Severe combined immunodeficient (SCID) mice that had been inoculated intraperitoneally with VV became sick and died within 1 month after infection. Following treatment with H961 at 100 mg/kg for 10 consecutive days (either via oral gavage or s.c. injection) VV-inoculated SCID mice were completely protected, for at least 3 months, against virus-induced morbidity and mortality. At that time, no virus could be recovered from the organs of these mice (as assessed by titration for infectious virus, a DNA hybridization assay, and a PCR for VV-specific sequences). Compound S2242 and its oral prodrug H961 could be useful in treatment of orthopoxvirus infections.
5-Ethyl-2'-deoxyuridine (EDU) is a potent and selective inhibitor of the replication of herpes simplex virus type 1 (HSV-1) and 2 (HSV-2), which is currently being pursued for the topical treatment of HSV-1 and HSV-2 infections in humans. Using [4-14C]EDU as the radiolabeled analogue of EDU, it was ascertained that, at antivirally active doses, EDU is phosphorylated to a much greater extent by HSV-infected Vero cells than by mock-infected cells. Within the HSV-1-infected cells, EDU was incorporated to a much greater extent into viral DNA than cellular DNA. Using varying doses of EDU, a close correlation was found between the incorporation of EDU into viral DNA, the inhibition of viral DNA synthesis, and the inhibition of virus yield. It is postulated that the selectivity of EDU as an antiviral agent depends on both its preferential phosphorylation by the virus-infected cell and its preferential incorporation into viral DNA. The latter than results in a suppression of viral DNA synthesis and, hence, shutoff of viral progeny formation.
Purpose To find the suitable parameters for selective laser sintering (SLS) of selected ferro‐based powders. These parameters will help to create products having appreciable strength shown by the highest density and good surface property. Design/methodology/approach Design of experiment (L9 Taguchi design) has been used to obtain the parameters in the minimum possible number of experiments. For finding the range of various parameters selected such as scan speed, scan spacing and layer thickness, some preliminary experiments have been performed. In order to carry out varied characterization for a given type of experiment, a number of samples have been made. Findings An attempt has been made to observe the correlation between applied laser energy and the properties of the laser‐sintered parts. Taguchi design has been useful and has given the optimized parameters. It has also been found that the infiltration increases the strength of the part substantially compared with the property of end‐used sintered product. Research limitations/implications The present set of experiments was limited by the range of supplied laser energy to the powder system, as the laser power could not be increased. Originality/value There is a need to search for alternative powders for manufacturing parts through SLS, which can alleviate the need to depend on customized powders, as these customized powders are limited to be used only with prescribed commercial SLS machines for their best performance. This drawback restricts their general use independent of any particular machine and it is, therefore, required to develop know‐how of powders and related process parameters for SLS. The present work is an effort in this direction in which laser sintering of a specially developed iron‐based powder mixture (Fe, Ni, Cu and Fe 3 P) has been tested on an SLS machine.
Several nucleoside analogues (penciclovir, lobucavir, dioxalane guanine [DXG], 1-beta-2,6-diaminopurine dioxalane [DAPD], L-FMAU, lamivudine) and acyclic nucleoside phosphonate analogues (adefovir, tenofovir) that are in clinical use, in clinical trials or under preclinical development for the treatment of hepatitis B virus (HBV) infections, were evaluated for their inhibitory effect on the replication of a la- mivudine-resistant HBV variant containing the methionine --> valine substitution (M550V) in the polymerase nucleoside-binding domain. The antiviral activity was determined in the tetracycline-responsive HepAD38 and HepAD79 cells, which are stably transfected with either a cDNA copy of the wild-type pregenomic RNA or with cDNA containing the M550V mutation. As expected, lamivudine was much less ( approximately 200-fold) effective at inhibiting replication of the M550V mutant virus than the wild-type virus. In contrast, adefovir, tenofovir, lobucavir, L-FMAU, DXG and DAPD proved almost equally effective against both viruses. A second objective of this study was to directly compare the antiviral potency of the anti-HBV agents in HepG2 2.2.15 cells (which are routinely used for anti-HBV drug-screening purposes) with that in HepAD38 cells. HepAD38 cells produce much larger quantities of HBV than HepG2 2.2.15 cells, and thus allow drug screening in a multiwell plate format. All compounds were found to be almost equally effective at inhibiting HBV replication in HepAD38 cells (as in HepG2 2.2.15 cells), except for penciclovir, which was clearly less effective in HepAD38 cells.
Interruption of the (I)n strand of (I)n.(C)n by unpaired bases [(U)] yielded mismatched analogues, (Ix,U)n.(C)n which were still effective as inducers of interferon, provided the I:U ratio (x) was equal or greater than 10. In highly sensitive interferon-induction systems such as primary rabbit kidney cells and human skin fibroblasts superinduced with cycloheximide and actinomycin D, (I10,U)n.(C)n and (I50,U)n.(C)n proved nearly as active as (I)n.(C)n. By virtue of their increased susceptibility to degradation by nucleases, (Ix,U)n.(C)n complexes with 10 less than or equal to x less than or equal to 50 may be expected not to persist as long in biological fluids as (I)n.(C)n, hence to induce fewer side effects.
