Antiviral compounds. XII. Antiviral activity of amidinohydrazones of alkoxyphenyl-substituted carbonyl compounds against influenza virus in eggs and in mice.
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Animals↗
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Results for “Antiviral compound”
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Antiviral compounds. III. Antiviral activities of 4,6-dichloro-2-aminophenol.
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Aniline Compounds↗
[Antiviral compounds. XVI. Antiviral activity of 1,2,4-triazines].
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Drug Resistance, Microbial↗
Inhibition of hepatitis A virus replication in vitro by antiviral compounds.
Forty antiviral compounds were screened for inhibitory effect on hepatitis A virus (HAV) antigen expression in the human hepatoma cell line PLC/PRF/5. Ribavirin, amantadine, glycyrrhizin, and pyrazofurin were selected in this screening test and were studied further. The selectivity indices of these four compounds, calculated as the ratio of 50% cytotoxic dose (determined by the trypan blue exclusion and by inhibition of [3H] leucine incorporation) to the 50% effective dose (determined by the viral antigen expression), were 4.6 and 3.0 with ribavirin, 5.3 and 5.9 with amantadine, 15.2 and 16.9 with glycyrrhizin, and 45.4 and 74.6 with pyrazofurin. All four compounds resulted in concentration-dependent reductions of HAV antigen expression and HAV infectivity. Ribavirin, amantadine, pyrazofurin, and glycyrrhizin emerged, from the present study, as promising candidates for chemotherapy of acute hepatitis A.
Antigens, Viral↗
New laboratory and clinical aspects of antiviral compounds.
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Antiviral Agents↗
In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds.
Effective antiviral agents are urgently needed to combat the possible return of severe acute respiratory syndrome (SARS). Commercial antiviral agents and pure chemical compounds extracted from traditional Chinese medicinal herbs were screened against 10 clinical isolates of SARS coronavirus by neutralisation tests with confirmation by plaque reduction assays. Interferon-beta-1a, leukocytic interferon-alpha, ribavirin, lopinavir, rimantadine, baicalin and glycyrrhizin showed antiviral activity. The two interferons were only active if the cell lines were pre-incubated with the drugs 16 h before viral inoculation. Results were confirmed by plaque reduction assays. Antiviral activity varied with the use of different cell lines. Checkerboard assays for synergy were performed showing combinations of interferon beta-1a or leukocytic interferon-alpha with ribavirin are synergistic. Since the clinical and toxicity profiles of these agents are well known, they should be considered either singly or in combination for prophylaxis or treatment of SARS in randomised placebo controlled trials in future epidemics.
Adult↗
Dissociation of an antiviral compound from the internal pocket of human rhinovirus 14 capsid.
WIN antiviral compounds bind human rhinovirus, as well as enterovirus and parechovirus, in an internal cavity located within the viral protein capsid. Access to the buried pocket necessitates deviation from the average viral protein structure identified by crystallography. We investigated the dissociation of WIN 52084 from the pocket in human rhinovirus 14 by using an adiabatic, biased molecular dynamics simulation method. Multiple dissociation trajectories are used to characterize the pathway. WIN 52084 exits between the polypeptide chain near the ends of betaC and betaH in a series of steps. Small, transient packing defects in the protein are sufficient for dissociation. A number of torsion-angle transitions of the antiviral compound are involved, which suggests that flexibility in antiviral compounds is important for binding. It is interesting to note that dissociation is associated with an increase in the conformational fluctuations of residues never in direct contact with WIN 52084 over the course of dissociation. These residues are N-terminal residues in the viral proteins VP3 and VP4 and are located in the interior of the capsid near the icosahedral 5-fold axis. The observed changes in dynamics may be relevant to structural changes associated with virion uncoating and its inhibition by antiviral compounds.
Antiviral Agents↗
Evaluation of the combination effect of different antiviral compounds against HIV in vitro.
3'-azido-3'deoxythymidine (AZT), a clinically used anti-HIV compound, was evaluated for antiviral effect on HIV infection in combination with other antiviral compounds in vitro. Interactions were evaluated by the median-effect principle and the isobologram technique. Synergistic effect was obtained by combining many evaluated antiviral agents with AZT. We observed a difference in the degree of synergism depending on the evaluated compound; the results indicate that compounds with the same target in the viral replicative cycle (ddI: 2',3'-dideoxyinosine, didanosine; d4T: 2',3'-dideoxy-2',3'-didehydrothymidine stavodine; TIBO: tetrahydro-imidazole-benzodiazepin) had a synergistic effect at all concentrations, agents that disturb the infectivity of virus (CAS: Castanospermine; AME: Amphotericin B Methyl Ester) exerted a strong synergistic effect at low concentrations, and finally compounds interfering with the adhesion/penetration process of virus (ConA: Concanavalin A; DS: dextran sulfate) were most potent with AZT when used in rather high concentrations. At this moment in the HIV epidemic, these observations suggest that combinations of antiviral compounds should be evaluated in clinical trials, with the major emphasis on nucleoside analogues and compounds influencing the infectivity of the virus.
Antiviral Agents↗
Susceptibility of vaccine strains of varicella-zoster virus to antiviral compounds.
Using a plaque reduction assay, we determined the 50% effective doses of six antiviral compounds against low- and high-passage viruses of the KMcC and Oka strains of varicella-zoster virus vaccine. The potency, as indicated by the ranges of 50% effective doses (micrograms per milliliter) of the antiviral compounds, in decreasing order was as follows: (E)-5-(2-bromovinyl)-2'-deoxyuridine, 0.0007 to 0.0035; 1-(2'-flouro-2-deoxy-beta-D-arabinofuranosyl)-5-iodocytosine, 0.0063 to 0.0091; aphidicolin, 0.092 to 0.180; acyclovir, 0.79 to 1.81; vidarabine, 0.62 to 2.10; and phosphonoformic acid, 8.18 to 16.4. Susceptibility to the various antiviral compounds was independent of passage level or strain. These data, along with the available in vivo data, indicate that varicella-zoster virus vaccine infections requiring antiviral therapy most probably would be treated as effectively as would natural varicella infections.
Antiviral Agents↗
Synthesis of 1-substitutes-5(6)-nitrobenzimidazoles as potential antiviral compounds.
The synthesis of 1-substituted, acyclic nucleoside derivatives of 5(6)-nitrobenzimidazoles and their pharmacological evaluation as antiviral compounds is described. The compounds were synthesized using 5(6)-benzimidazole as starting material with the appropriate chloromethylated substituted alcohols to obtain analogues of the known antiviral compounds, Acyclovir and Ganciclovir. The antiviral activity of these compounds was evaluated using strains of Herpes Simplex 1 and Poliovirus 1 and were found to be inactive as antiviral compounds under the testing conditions employed.
Antiviral Agents↗
A screening assay for antiviral compounds targeted to the HIV-1 gp41 core structure using a conformation-specific monoclonal antibody.
The human immunodeficiency virus type 1 (HIV-1) gp41 plays an important role in membrane fusion between viruses and target cells. The gp41 ectodomain contains two heptad repeat regions adjacent to the N and C-termini. Peptides derived from these two regions, designated N and C-peptides, are potent inhibitors of HIV-1 infection and can interact with each other to form a six-stranded coiled-coil, representing the fusogenic core structure of gp41. A monoclonal antibody was generated, designated NC-1, which specifically binds to the complex formed by the N and C-peptides, but not to the individual peptides. An enzyme linked immunosorbent assay (ELISA) was developed using NC-1 for detecting complex formed by N and C-peptides and for screening of organic compounds for antiviral agents that may interfere with complex formation and inhibit HIV-1 infection. Single point mutations in the C-peptides abolish the complex formation also eliminate their anti-HIV-1 activity. A phenylazo-naphthalene sulfonic acid derivative, designated ADS-J1, was found to inhibit both formation of NC-1 detectable complex and HIV-1-mediated membrane fusion, suggesting that the described ELISA is applicable to rapid screening of libraries of organic compounds for HIV-1 inhibitors targeted to the HIV-1 gp41 core structure.
Amino Acid Sequence↗
Parameters for the characterization of antiviral compounds in cell culture experiments.
The antiviral activity of seven compounds against the replication of herpes simplex and rubella viruses in cell culture was examined using different parameters as follows: cytotoxicity (CT) of compounds giving 50 and 0% (CT50, CT0) reduction in cell growth; the slope of the curve of CT; decrease in virus infectivity titer in the presence of CT50 and CT0 concentrations of the compound (D); maximum amount of the compound giving zero inhibition of virus replication (I0); therapeutic index (TI); further decrease in the virus titer after withdrawal of the compound from the medium (DS); and the 'shadow' showing the degree of virus replication after withdrawal of the compound from the medium. The higher the values of D, DS, TI, and the lower the values of I0 and the 'shadow', the more valuable the antiviral compound. These parameters characterize the CT, the potency and the specificity of the antiviral compound and they may be used in antiviral tests to select new and more specific antiviral agents.
Antiviral Agents↗
Efficacy of antiviral compounds in human herpesvirus-6-infected glial cells.
The beta-herpesvirus human herpesvirus-6 (HHV-6) is becoming increasingly recognized as an important pathogen in immunocompromised patients, particularly in post bone marrow transplant (BMT). Reactivation of latent HHV-6 resulting in encephalitis has been reported in BMT and stem cell transplant (SCT) patients. The development of HHV-6 encephalitis can be a fatal complication, the frequency of which is increasing likely due to improved diagnosis with quantitative polymerase chain reaction (PCR) of cerebrospinal fluid. There are currently no antiviral compounds approved for HHV-6, nor have any controlled clinical trials been conducted. The frequency and severity of HHV-6 encephalitis in both immunocompetent and immunocompromised patients necessitates studies on the usefulness of currently available anti-viral compounds. The authors compared the antiviral efficacy of four drugs currently used for cytomegalovirus (CMV) infection, a beta-herpesvirus sharing homology with HHV-6. In HHV-6A- and HHV-6B-infected T cells, acyclovir, ganciclovir, foscarnet, and cidofovir exhibited antiviral activity consistent with that published in other studies. In HHV-6-infected human astrocytes (U251), however, only foscarnet and cidofovir exhibited antiviral activity and this effect was restricted to infection with HHV-6 variant A. In pathological brain sections from patients with neurological disorders such as multiple sclerosis and epilepsy, HHV-6 has been localized to glial cells. Determination of antiviral activity in human glial fibrillary acidic protein (GFAP)-positive astrocytes of currently used antiviral compounds is essential for potential treatment of HHV-6 and neurological disorders. Our data highlight the necessity for further study of antiviral compound in HHV-6-infected glial cells as well as the development of more selective compounds for HHV-6.
Antiviral Agents↗
Molecular dynamics simulations of human rhinovirus and an antiviral compound.
The human rhinovirus 14 (HRV14) protomer, with or without the antiviral compound WIN 52084s, was simulated using molecular dynamics and rotational symmetry boundary conditions to model the effect of the entire icosahedral capsid. The protein asymmetrical unit, comprising four capsid proteins (VP1, VP2, VP3, and VP4) and two calcium ions, was solvated both on the exterior and the interior to fill the inside of the capsid. The stability of the simulations of this large system (~800 residues and 6,650 water molecules) is comparable to more conventional globular protein simulations. The influence of the antiviral compound on compressibility and positional fluctuations is reported. The compressibility, estimated from the density fluctuations in the region of the binding pocket, was found to be greater with WIN 52084s bound than without the drug, substantiating previous computations on reduced viral systems. An increase in compressibility correlates with an entropically more favorable system. In contrast to the increase in density fluctuations and compressibility, the positional fluctuations decreased dramatically for the external loops of VP1 and the N-terminus of VP3 when WIN 52084s is bound. Most of these VP1 and VP3 loops are found near the fivefold axis, a region whose mobility was not considered in reduced systems, but can be observed with this simulation of the full viral protomer. Altered loop flexibility is consistent with changes in proteolytic sensitivity observed experimentally. Moreover, decreased flexibility in these intraprotomeric loops is noteworthy since the externalization of VP4, part of VP1, and RNA during the uncoating process is thought to involve areas near the fivefold axis. Both the decrease in positional fluctuations at the fivefold axis and the increase in compressibility near the WIN pocket are discussed in relationship to the antiviral activity of stabilizing the virus against uncoating.
Antiviral Agents↗
New antiviral compounds.
Several potent and selective antiviral agents against herpes virus infections have been developed. However, the majority of compounds against other viral diseases has not yet reached such high standard. Based on progress in molecular virology it can, however, be anticipated that similar concepts of selective inhibition will also be developed for other virus groups. In addition to virus-induced enzymes, viral proteins other than enzymes with specific activities will be identified. The identification of active sites will lead to the design of new and specific inhibitors. Moreover, studies on the mode of action of the huge number of known antiviral compounds may provide the basis for new and potent approaches to specific virus chemotherapy. New inhibitors of viral replication may also be derived from 2'-5'A and other mediators of the interferon induced antiviral state. However, since 2'-5'A does not enter cells, is rapidly degraded by phosphodiesterases, and affects viral and cellular protein synthesis, only analogs which do not have these disadvantages may qualify as antiviral drugs. In addition to refinements at the molecular level quantitative assays for a better evaluation of antiviral agents for clinical use are required. For clinical trials, rapid diagnosis, early initiation of treatment, and quantitative evaluation of the antiviral effects of a drug need to be developed. Moreover, new methods of drug delivery and/or drug targeting will improve potency and selectivity of antiviral compounds. Drug carriers have already successfully been used in cancer therapy (Poste and Fidler, 1981) they should be also applicable to virus chemotherapy. Finally, a better understanding of the pathogenesis and the natural course of viral diseases will contribute to the development of more effective and safe antiviral agents.
Adenine Nucleotides↗
Effect of the antiviral compound MDL 20,610 on some aspects of murine immune function.
At physiologically relevant concentrations an antiviral compound should not perturb the host's ability to mount an immune response against the infecting virus or some other opportunistic pathogen. The purpose of this study was to evaluate the immunomodulatory activity of the antiviral compound MDL 20,610 using murine models. When tested in vitro at the limit of aqueous solubility (6 microM), MDL 20,610 has no significant effect on neutrophil function as assessed by cell migration against FMLP and LTB4 gradients, myeloperoxidase secretion or 0.-2 production. In addition, 6 microM MDL 20,610 has no significant effect on macrophage function as determined by 0.-2 production, Ia and Mac-1 antigen expression and expression of Fc gamma receptors. Finally, MDL 20,610 does not significantly affect in vivo (1-100 mg/kg/day) NK cell activity or DTH to oxazolone; but treatment of mice with 50 or 100 mg MDL 20,610/kg/day significantly (P less than 0.01) enhances SRBC IgM antibody synthesis. These data indicate that MDL 20,610 is relatively devoid of immunomodulatory activity.
Adjuvants, Immunologic↗
Two groups of rhinoviruses revealed by a panel of antiviral compounds present sequence divergence and differential pathogenicity.
A variety of chemically different compounds inhibit the replication of several serotypes of rhinoviruses (common-cold viruses). We noticed that one of these antiviral compounds, WIN 51711, had an antiviral spectrum clearly distinctive from a consensus spectrum or other capsid-binding compounds, although all of them were shown to share the same binding site. A systematic evaluation of all known rhinovirus capsid-binding compounds against all serotyped rhinoviruses was therefore initiated. Multivariate analysis of the results revealed the existence of two groups of rhinoviruses, which we will call antiviral groups A and B. The differential sensitivity of members of these groups to antiviral compounds suggests the existence of a dimorphic binding site. The antiviral groups turned out to be a reflection of a divergence of rhinovirus serotypes on a much broader level. Similarities in antiviral spectra were highly correlated with sequence similarities, not only of amino acids lining the antiviral compound-binding-site, but also of amino acids of the whole VP1 protein. Furthermore, analysis of epidemiological data indicated that group B rhinoviruses produced more than twice as many clinical infections per serotype than group A rhinoviruses did. Rhinoviruses belonging to the minor receptor group were without exception all computed to lie in the same region of antiviral group B.
Amino Acid Sequence↗
Antiviral compounds. 1. Structure-activity relationship of some antiviral enediones derived from aldehydo sugars.
A series of aldehydo sugars was subjected to condensation reactions with active methylene compounds. Acetylacetone was condensed with 2,4-O-benzylidene-3,5-O-dibenzoyl-D-ribose (1), 2,4:3,5-O-dibenzylidene-D-ribose (6), 2,3,4,5-tetraacetyl-D-ribose (7), and 2,3,4,5,6-pentaacetyl-D-glucose (9) to yield 3-ylidene-2,4-pentanedione derivatives 2, 11, 12, and 13, respectively. Sugar derivatives 1 and 6 were also condensed with benzoylacetone to give 14 and 18, with acetoacetanilide to give 16 and 19, with malononitrile to give 17 and 20, and with alpha-(gamma-butyrolactonylidene)triphenylphosphorane to give 21 and 22, respectively. Condensation of 1 with dibenzoylmethane gave 15. The double bond in compounds 2 and 11 was saturated by hydrogenation to give 23 and 24. All alpha, beta-unsaturated carbonyl compounds obtained exhibited antiviral activity and cytotoxicity. Compound 11 was found to have the most significant and selective antiviral activity against herpes simplex virus.
Alkenes↗