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PubMed1994

A C2 symmetry-based HIV protease inhibitor, A77003, irreversibly inhibits infectivity of HIV-1 in vitro.

A C2 symmetry-based HIV protease inhibitor, A77003, exerts potent antiviral activity against a wide spectrum of HIV isolates in vitro. In this study, we asked whether A77003 could cause irreversible conformational changes to HIV-1, whether the amounts of viral RNA and p24 capsid protein per virion were altered, and how the infectivity of the virus produced in the presence of the drug was affected. We found that the number of viral particles and per-virion viral RNA content of the virus produced in the presence of A77003 did not significantly differ from those of the virus produced in the absence of the drug, whereas significant morphological changes were observed as assessed by transmission electron microscopy. However, the virus produced in the presence of A77003 contained substantially less p24gag protein per virion particle as compared to those produced in the absence of the drug or in the presence of AZT. Virions produced in the presence of A77003 showed up to 50-fold less infectious capability in subsequent tissue culture than control virions produced in the absence of drug or in the presence of AZT. This reduction in infectivity was maintained for at least 10 days in culture. The present data suggest that A77003 impairs HIV-1 protease-mediated Gag processing, interferes with the assembly and maturation of the virus, and leads to an irreversible loss of the infectivity of the virus, although a low but positive level of reversion to infectivity during the 10-day assay occurs. These features of A77003 (and perhaps similar HIV protease inhibitors as well) anti-HIV activity should represent desirable properties for antiviral therapy of AIDS and related diseases.

Antiviral Agents↗
PubMed1990

Quantitative estimates of N-nitrosotrimethylurea formation in the porcine stomach.

Gastric formation of N-nitrosotrimethylurea (NTMU) was quantified by repeated sampling of the gastric contents of full-sized fistulated pigs after the addition of 250 mumol trimethylurea (TMU) and 25-125 mumol nitrite. Maximum gastric nitrite concentration was 100-500 microM based on the gastric volume and amount of added nitrite, which is within the range reported in human gastric contents. The total amount of NTMU formed over time was quantified by estimating both the NTMU concentration and gastric volume using multiple additions of polyethylene glycol. Administration of 25 mumol of nitrite resulted in the formation of 320 nmol of NTMU. The total amount of NTMU formed was linearly related to nitrite dose. Conversion of nitrite to NTMU was of the order of 1-3%. Potassium thiocyanate (200-2000 mumol) had no effect on NTMU formation when given immediately preceding 75 mumol nitrite. Ascorbic acid at 225 and 341 mumol (0.66 and 1.0 of the recommended dietary allowance) inhibited nitrosation of TMU by an average of 54 and 84%. A pig with an average gastric pH of 1.9 formed 4.5-fold more NTMU than did a second pig at pH 4.8. These results suggest that low micromolar amounts of N-nitrosoureas can be formed in the normal stomach when nitrite is consumed in amounts to which humans are commonly exposed.

Animals↗
PubMed1991

Gastric nitrate reduction and nitrosation of trimethylurea in swine treated with pentagastrin or cimetidine.

Swine were treated with cimetidine in order to quantify the reduction of nitrate to nitrite and the gastric formation of N-nitrosotrimethylurea (NTMU) under conditions similar to those in the achlorhydric human stomach. Gastric-fistulated swine were instilled with 6.0 mmol of nitrate in 50 ml water, after which gastric nitrate, nitrite and pH were monitored. Trimethylurea, 250 mumol in 50 ml water, was instilled via the fistula 10 min following the peak gastric nitrite concentration. Similar experiments were conducted with pentagastrin-stimulated animals, in order to quantitate the effect of gastric pH and microflora on the presence of nitrate, nitrite and NTMU formation. The stomachs of cimetidine-treated pigs (elevated pH) were colonized by nitrate reductase organisms to levels of 10(4)-10(7)/ml gastric fluid. Gastric nitrite concentration in cimetidine-treated animals reached a maximum of 370-2085 microM, 60 min following the nitrate dose. Trimethylurea was only marginally nitrosated (less than 0.1 mumol/l gastric fluid) in cimetidine- or pentagastrin-stimulated animals. The low yield of NTMU at elevated pH, in the presence of substantial nitrite, suggests that the nitrate-reducing bacteria present in the porcine stomach did not catalyze trimethylurea nitrosation in vivo.

Animals↗
PubMed1977

High pressure liquid chromatographic analysis of Oryzalin and other selected herbicides.

Procedures are described for the analysis of Oryzalin, Tebuthiuron, and several other selected dinitroaniline herbicides by high-pressure liquid chromatography (HPLC). Quantitation of Oryzalin and small concentrations of chemical impurities from the production process can be performed rapidly. Linearity and reproducibility are discussed and comparisons to other methods are made.

Chromatography, High Pressure Liquid↗
PubMed1995

Reduction of the in vitro activity of A77003, an inhibitor of human immunodeficiency virus protease, by human serum alpha 1 acid glycoprotein.

Since plasma protein binding of antiinfectives can adversely affect drug activity, the effect of serum proteins on the in vitro antiviral activity of A77003, a human immunodeficiency virus type 1 (HIV) protease inhibitor, was investigated. In vitro, A77003 is effective in both acute and chronic infection in 10% fetal bovine or human serum. As the concentration of human serum was increased to 50%, antiviral efficacy decreased 3- to 6-fold. Purified human alpha 1 acid glycoprotein (alpha 1-AGP) at physiologic concentrations (0.5-2 mg/mL) dose-dependently reduced the antiviral activity of A77003. alpha 1-AGP at 1 mg/mL also antagonized the anti-HIV activity of A77003-zidovudine combinations. Therefore, higher concentrations of HIV protease inhibitors than would be predicted, on the basis of in vitro activity in the absence of physiologic concentrations of binding protein, may be required to effectively limit viral replication in vivo.

Antiviral Agents↗
PubMed2006

Effect of physiological concentration of urea on the conformation of human serum albumin.

We report that the presence of very low concentrations (<0.1 M) of urea, a widely used chemical denaturant, induces structure formation in the water-soluble globular protein human serum albumin (HSA) at pH 7. We have presented results suggesting an almost 8% and 5% increase in alpha-helix in the presence of 10 mM urea (U) and 20 mM monomethylurea (MMU), respectively. Far and near-UV circular dichroism studies along with tryptophan fluorescence and 1-anilino-8-naphthalenesulphonicacid (ANS) binding support our view. We hypothesize that both U and MMU, at such low concentrations, modify the solvent structure, increase the dielectric constant and consequently increase hydrophobic forces resulting in enhanced alpha-helical content. The implications of these results of the lower urea regime are significant because the physiological blood urea ranges from 2.5 to 7.5 mM.

Anilino Naphthalenesulfonates↗
PubMed1983

1,1,3,3-Tetramethylurea and triethanolamine as a new useful matrix for fast atom bombardment mass spectrometry of gangliosides and neutral glycosphingolipids.

Analysis of gangliosides from bovine brain was successfully performed by a newly developed method of fast atom bombardment mass spectrometry (FAB-MS). The use of triethanolamine with a few drops of 1,1,3,3-tetramethylurea as the matrix solution gave intense molecular ions of intact gangliosides tested, namely, GM1 and GD1a, corresponding to (M + Na)+ and (M + 2Na-H)+. Glycerol, that is usually used as a matrix solution for FAB-mass spectrometry, was not suitable for the analysis of gangliosides. Along with the molecular ion species, the ions pertaining to the carbohydrate sequence also appeared on the spectrum. The method was found to be useful for structural analysis using intact molecules of gangliosides and neutral glycosphingolipids.

Animals↗
PubMed1998

Estimates of relative binding free energies for HIV protease inhibitors using different levels of approximations.

Although the free energy perturbation approach is a rigorous method for estimating the relative binding free energy between an enzyme and its inhibitors, it is computationally expensive. This paper examines the accuracy at different levels of approximations, following the series expansion of free energy derived by Aqvist et al. Level-0 calculates only the enzyme-inhibitor interaction energy at the minimum energy configuration without solvent. In Level-0MD, the inhibitor configurations are sampled by molecular dynamics. These levels assume that the second- and higher order terms in the series expansion can be neglected and that the interaction energies in the bound and unbound states are equal. Level-1 does not assume equal interaction energies in the bound and unbound states. Level-1S includes the solvent contribution but both enzyme and inhibitor are fixed. In Level-1SMD, the inhibitor configurations are sampled by molecular dynamics. Level-2SMD retains the second-order term. We chose seven HIV-1 protease inhibitors for study: A77003, A76889, A76928, A78791, A74704, JG365 and MVT101. Level-0 and Level-0MD were found to give essentially the same relative interaction energies by using the AMBER force field, suggesting that fixing atomic positions may be a good approximation in some cases. However, as expected, Level-0 or Level-0MD gave poor predictions for the relative binding free energies between hydrophobic inhibitors (e.g. A77003) and more hydrophilic inhibitors (e.g. JG365). Level-1SMD produced a much better correlation between calculated and experimental results. Inclusion of the second-order term did not improve the accuracy.

Chemical Phenomena↗
PubMed1995

Inhibition of endotoxin-induced microvascular leakage by a platelet-activating factor antagonist and 5-lipoxygenase inhibitor.

The sepsis syndrome is associated with increased vascular permeability. Mediators may include platelet-activating factor (PAF) and leukotrienes. We conducted experiments in the hamster cheek pouch to determine the ability of a 5-lipoxygenase (5-LO) inhibitor and a PAF antagonist to attenuate the increase in microvascular permeability that results from tissue exposure to endotoxin. Endotoxin (Escherichia coli serotype 0127:B8) or saline was administered to the surface of the cheek pouch following systemic pretreatment with either the 5-LO inhibitor (Abbott-77523; 20 mg/kg, i.v.) or PAF antagonist (Abbott-84768: 1 mg/kg, i.v.). In control hamsters, endotoxin induced a large increase in fluorescein isothiocyanate-dextran leakage into the cheek pouch interstitium. This leakage was not associated with increased leukocyte rolling or adhesion to venular endothelium. In contrast, groups pretreated with the PAF antagonist or the 5-LO inhibitor showed little or no leakage in response to endotoxin. Therefore, PAF and leukotrienes are important mediators of endotoxin-induced increases in microvascular permeability to macromolecules.

Analysis of Variance↗
PubMed1992

Apparent specific volumes of some dipeptides (containing L-valine and L-leucine in aqueous alkylurea solutions).

The apparent molal volumes of nine dipeptides containing glycine, L-valine, and L-leucine have been determined in methyl, N,N'-dimethyl and ethylurea solutions from precise density measurements. Limiting partial molal volumes. V2(0), at various solute concentrations have also been calculated. The experimental values of V2(0) in water agree reasonably well with those calculated as the sum of V2(0) of both acids after accounting for the electrostrictive effect and loss of water. There is no correlation between the values of V2(0) of individual dipeptides in alkylureas which means that the intrinsic volume and the electrostrictive effect make the largest contribution to V2(0). The contribution from other effects is within the limit of experimental error. The volumes of transfer from water to alkylurea solutions are all positive and reflect by and large the electrostrictive effect.

Amino Acid Sequence↗
PubMedDate not supplied

Assessing herbicide concentrations in the saturated and unsaturated zone of a Chalk aquifer in southern England.

The behavior of the herbicides isoproturon (IPU) and chlortoluron (CTU) in ground water and shallow unsaturated zone sediments were evaluated at a site situated on the Chalk in southern England. Concentrations of IPU in ground water samples varied from < 0.05 to 0.23 microgram/L over a five-year period of monitoring, and were found to correlate with application of the pesticide. Concentrations of pesticides in ground water samples collected during periods of rising water table were significantly higher than pumped samples and suggest that rapidly infiltrating recharge water contains higher herbicide concentrations than the native ground water. Significant variations in herbicide concentrations were observed over a three-month period in ground water samples collected by an automated system, with concentrations of IPU ranging from 0.1 to 0.5 microgram/L, and concentrations of a recent application of CTU ranging from 0.2 to 0.8 microgram/L. Different extraction methods were used to assess pore water concentrations of herbicides in the unsaturated zone, and samples were analyzed by standard HPLC analysis and immunoassay (ELISA) methods. These data indicated highly variable concentrations of herbicide ranging from 4 to 200 g/ha for HPLC and 0.01 to 0.04 g/ha for ELISA, but indicate a general pattern of decreasing concentrations with depth. The results of this study indicate that transport of IPU and CTU through the unsaturated zone to shallow ground water occurs and that this transport increases immediately following herbicide application. Measured concentrations of herbicides are generally lower than specified by the European Union Drinking Water Directive, but are observed to spike above this limit. These results imply that, while delivery of pesticides to ground water can occur as a result of normal agricultural practices, the impact on potable supplies is likely to be negligible due to the potential for degradation during the relatively long travel time through the unsaturated zone and high degree of dilution that occurs within the aquifer. As a result of the wide variation in concentrations detected by different techniques, it is suggested that for future site investigations more than one sampling strategy be employed to characterize the occurrence of pesticide residues and elucidate the transport mechanisms.

Calcium Carbonate↗
PubMed1975

Reduction of gastric carcinogens with ascorbic acid.

The formation of nitrite from nitrate was studied in potatoes incubated at room temperature. After 24 hours of incubation at 25 degrees, 112 ppm and 373 ppm of nitrite formed in homogenized cooked potatoes containing 284 ppm and 584 ppm of nitrate, respectively. In homogenized fresh potatoes incubated at 21 degrees and containing 284 ppm of nitrate, 103 ppm of nitrate formed within 24 hours. During the period of nitrite formation, nitrate levels decreased sharply, indicating that reduction of nitrate to nitrite occurred. Incubation at 2 degrees completely prevented nitrite formation in all cases. The formation of methylnitrosourea from added methylurea and nitrite was observed in potato incubated under simulated gastric conditions (37 degrees, pH 1.5). An ascorbate-nitrite mole ratio of 4 gave a 93% inhibition of methylnitrosourea formation. Ascorbate reacted directly with nitrite in potato incubated under identical conditions, yielding a 43% decrease in nitrite concentration. Ascorbate did not react with methylurea or the product, methylnitrosourea.

Ascorbic Acid↗
PubMed2001

Selective cleavage of D-Ala-D-Lac by small molecules: re-sensitizing resistant bacteria to vancomycin.

Pathogenic enterococci are becoming resistant to currently available antibiotics, including vancomycin, the drug of last resort for Gram-positive infections. Enterococci pose a significant public health threat, not least because of the risk of transferring vancomycin resistance to the ubiquitous Staphylococcus aureus. Vancomycin resistance is manifested by cell wall peptidoglycan precursors with altered termini that cannot bind the antibiotic. Small molecules with well-oriented nucleophile-electrophile assembly and complementary chirality to the peptidoglycan termini were identified as catalytic and selective cleavers of the peptidoglycan precursor depsipeptide. These molecules were tested in combination with vancomycin and were found to re-sensitize vancomycin-resistant bacteria to the antibiotic.

Alanine↗