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ABSTRACT: Despite the advances in biomedical knowledge, there remain many challenging and significant unsolved problems among which are included viral pathogenesis and antiviral therapy, as main topics in human health. On this respect, for instance, our knowledge about human immunodeficiency virus and AIDS is still insufficient to deal with problems of immense significance, such as the possible "natural cure" for a chronic infection or the induction of protective immunity against this agent. At the same time, new viral diseases of humans and animals continue to emerge or re-emerge, due to changes in host susceptibility and/or in virus virulence as well as to re-introduction of a virus that had disappeared from a defined population. These changes, at least in part, may appear as a consequence of antiviral therapies and lead to the selection of viral mutants. Moreover, taking into account that viruses have been studied as causative agents of conspicuous diseases a broad spectrum of uncertainty is still present when unapparent persistent infections are considered. Based on Hippocrates (460-357 b.C.E) natural philosophy, "Natura Morborum Medicatrix" which represents the natural healing force, i.e.: "Nature cures diseases"; and "Similia Similibus Curantur" which means "like cure like", we propose the use of natural compounds with chemical structures similar to cellular membrane components. On this approach, sulfated polysaccharides obtained from marine algae may act as a driving force for the emergence of attenuated viruses, enabling this way a practical approach for preventive therapies for herpes simplex virus infection. At the same time, viruses would be creative tools and their contribution by adding new genetic identity to their host are set points of genesis in the growth of the tree of life.
Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 02/2011; 11(5):798-802. · 3.22 Impact Factor
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ABSTRACT: The promyelocytic leukemia protein (PML) forms nuclear bodies (NB) that can be redistributed by virus infection. In particular, lymphocytic choriomeningitis virus (LCMV) influences disruption of PML NB through the interaction of PML with the arenaviral Z protein. In a previous report, we have shown that the disulfide compound NSC20625 has antiviral and virucidal properties against arenaviruses, inducing unfolding and oligomerization of Z without affecting cellular RING-containing proteins such as the PML. Here, we further studied the effect of the zinc-finger-reactive disulfide NSC20625 on PML-Z interaction. In HepG2 cells infected with LCMV or transiently transfected with Z protein constructs, treatment with NSC20625 restored PML distribution from a diffuse-cytoplasmic pattern to punctate, discrete NB which appeared identical to NB found in control, uninfected cells. Similar results were obtained in cells transfected with a construct expressing a Z mutant in zinc-binding site 2 of the RING domain, confirming that this Z-PML interaction requires the integrity of only one zinc-binding site. Altogether, these results show that the compound NSC20625 suppressed Z-mediated PML NB disruption and may be used as a tool for designing novel antiviral strategies against arenavirus infection.
Biochemical and Biophysical Research Communications 02/2010; 393(4):625-30. · 2.48 Impact Factor
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ABSTRACT: The zinc finger proteins have fascinated many research groups because of their modular assembly, broad range of biological functions and more recently because they are attractive targets for antiviral therapy. The zinc finger domain is a very stable structural element whose hallmark is the coordination of a zinc ion by several amino acid residues, usually cysteines and histidines. These structural motifs are associated with protein-nucleic acid recognition as well as protein-protein interactions. The biological function of the zinc finger proteins is strongly dependent on the zinc ion, which assure integrity and stability. Thus, the disruption of critical zinc finger viral proteins represents a fundamentally new approach to inhibit viral replication in the absence of mutations leading to drug resistance phenotypes. This review summarizes the drug design and potential therapeutic applications of viral zinc fingers disrupting agents for the control of viral diseases.
Infectious Disorders - Drug Targets(Formerly Current Drug Targets - Infectious Disorders) 10/2007; 7(3):204-12.
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ABSTRACT: The partially cyclized mu/nu-carrageenan 1C3, isolated from the red seaweed Gigartina skottsbergii, was previously shown to be a potent inhibitor of the in vitro replication of Herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). Here the protective effect of 1C3 in a murine model of intraperitoneal ( i. p.) HSV-1 infection was evaluated. OF1 mice were i. p. infected with 5 x 10 (5) PFU of HSV-1 KOS strain, and the effects of different treatments with 1C3 were studied. When 30 mg/kg of body weight of 1C3 was administered by the i. p. route immediately after HSV-1 infection, 87.5 % survival of the animals was achieved (p < 0.005), associated with a delay in the mean day of death in 1C3-treated non-surviving mice. Animal survival was not improved when multiple doses of 1C3 were also given in the period 1 - 48 h post-infection, and no protection was afforded when treatment was started after 24 h of infection. When virus and compound were injected by different routes, i. p. and intravenous ( i. v.), respectively, a still significant protection was achieved (40 % survival, p < 0.05). No toxicity of 1C3 for the animals was recorded. The pharmacokinetic properties were analyzed after injection of 1C3 into the tail vein by monitoring of [ (3)H]-1C3 in plasma and organs and by a bioassay of the anti-HSV-1 activity remaining in serum after non-radioactive 1C3 inoculation. A very rapid disappearance of the compound from the blood was observed since only 5.9 - 0.9 % of the radioactivity of the initially administered [ (3)H]-1C3 appeared in the plasma between 5-300 minutes after administration. A transient peak of radioactivity was detected in the kidney 15 minutes after inoculation. The bioassay confirms the presence of the compound circulating in a biologically active form up to 1 hour after injection.
Planta Medica 02/2006; 72(2):121-5. · 2.15 Impact Factor
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ABSTRACT: Two homogeneous sulfated polysaccharides obtained from the red seaweeds Gymnogongrus griffithsiae and Cryptonemia crenulata, the kappa/iota/nu carrageenan G3d and the dl-galactan hybrid C2S-3, were assayed for their antiviral properties against the four serotypes of dengue virus (DENV) in different host cell types. Both seaweed derivatives were selective inhibitors of DENV-2 multiplication in Vero cells with inhibitory concentration 50% (IC50) values around 1 microg/ml and selectivity indices > 1000. The compounds had a lower antiviral effect against DENV-3 (IC50 values in the range 13.9-14.2 microg/ml), an even lower effect against DENV-4 (IC50 values in the range 29.3 to > 50 microg/ml) and were totally inactive against DENV-1. With respect to the host cell, the polysulfates were inhibitors of DENV-2 and DENV-3 in the human hepatoma HepG2 and foreskin PH cells, with similar antiviral effectiveness as in Vero cells, but were totally inactive in mosquito C6/36 HT cells. Mechanistic studies demonstrated that G3d and C2S-3 were active DENV-2 inhibitors only when added together with the virus or early after infection, and both initial processes of virus adsorption and internalization are the main targets of these compounds. Therefore, the variations in antiviral activity of the polysaccharides depending on the viral serotype and the host cell may be ascribed to differences in the virus-cell interaction leading to virus entry.
Antiviral Research 06/2005; 66(2-3):103-10. · 4.30 Impact Factor
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ABSTRACT: In the present study, the protective effect of 1T1, a lambda-carrageenan extracted from the red seaweed Gigartina skottsbergii was evaluated in a murine model of herpes simplex virus type 2 (HSV-2) genital infection. Six to eight-week-old female BALB/c mice were intravaginally inoculated with a lethal dose of HSV-2 (MS strain) and pre- or post-infection treated with different doses of a 10mg/ml solution of 1T1. A single topical administration of 1T1 shortly before infection of BALB/c mice with HSV-2 protected 9 out of 10 mice from HSV-2-induced lesions and mortality, compared with only 10% survival in control mice. In addition, 1T1 produced a total blockade in virus shedding in the vaginal secretions. When 1T1 pre-treatment was reinforced with a second dose 2h after infection, total protection was observed even when the prophylactic administration had taken place at 60min before infection. The irreversible virucidal action of 1T1 against herpes virus seems to be responsible of its protective effect against virus replication and mortality following vaginal HSV-2 infection.
Antiviral Research 12/2004; 64(2):137-41. · 4.30 Impact Factor
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ABSTRACT: Essential oils obtained from eight aromatic plants of San Luis Province, Argentina, were screened for virucidal activity against herpes simplex virus type 1 (HSV-1), Junin virus (JUNV) and dengue virus type 2 (DEN-2). The most potent inhibition was observed with the essential oil of Lippia junelliana and Lippia turbinata against JUNV with virucidal concentration 50% (VC(50)) values in the range 14-20 ppm, whereas Aloysia gratissima, Heterotheca latifolia and Tessaria absinthioides inhibited JUNV in the range 52-90 ppm. The virucidal activity was time- and temperature-dependent. The essential oils of A. gratissima, Artemisia douglasiana, Eupatorium patens and T. absinthioides inactivated HSV-1 at 65-125 ppm. However, only A. douglasiana and E. patens had any discernible effect on DEN-2 infectivity with VC(50) values of 60 and 150 ppm, respectively.
Phytotherapy Research 12/2003; 17(9):1073-5. · 2.09 Impact Factor
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ABSTRACT: Several disulfide-based compounds, including intermolecular aromatic disulfides of the type Ph-S-S-Ph and dithianes with the sulfur atoms tethered in a ring structure, have shown effective inhibitory activity against the arenaviruses Junin (JUNV), agent of Argentine hemorrhagic fever, and Tacaribe (TCRV). These compounds showed a strong virucidal effect with inactivating concentration 50% (IC(50)) values in the range 0.6-5.0 microM, and also were effective to reduce virus yields from infected cells. The mode of inactivating action of two active compounds, the aromatic bis disulfide NSC20625 and the dithiane NSC624152, was further studied. Both compounds were able to inactivate arenaviruses after a few minutes of direct contact with virions, in a concentration- and time-dependent manner. The ability of drug-treated virus to perform several steps of the replication cycle was analyzed. The killed virus particles were found to bind and enter to Vero cells with the same efficacy as infectious native virions, but the ability of inactivated virions to synthesize viral proteins in Vero cells was abolished. Thus, treatment of JUNV and TCRV with these compounds destroyed virion infectivity, generating particles which entered the host cell but were unable to complete the viral biosynthetic processes.
Antiviral Research 10/2002; 55(3):437-46. · 4.30 Impact Factor
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ABSTRACT: Natural carrageenans of diverse structural types isolated from the red seaweed Gigartina skottsbergii were recently identified as potent and selective inhibitors of herpes simplex virus types 1 and 2 (HSV-1 and -2). The mu/nu-carrageenan 1C3 was tested in vitro for its ability to select resistant variants. After serial passages of HSV-1 strain F in Vero cells in the presence of increasing concentrations of 1C3, viruses emerged that were approximately 2- to 10-fold more resistant to 1C3 inhibition than parental virus; these viruses formed large plaques with an altered syncytial phenotype (1C3-syn). Plaque-purified syncytial variants isolated from passages 13 and 14 have shown variable levels of resistance to 1C3, as well as to the other antiviral carrageenans isolated from G. skottsbergii and to other sulfated polysaccharides with known antiviral activity, such as heparin and dextran sulfate 8000, but all the clones were susceptible to acyclovir. The syn phenotype was not related to polysaccharide resistance. All the 1C3-syn variants formed large syncytia in Vero and CV-1 cells but did not induce fusion in other cell types. The growth efficiency in Vero cells, as well as the virulence for mice by intracerebral or intraperitoneal inoculation of 1C3-syn variants, showed no significant alterations in comparison with the parental virus. The syncytial properties were not affected by cyclosporine or melittin, suggesting that an alteration on glycoprotein gB could be responsible for the syn phenotype induced by 1C3.
Journal of Medical Virology 10/2002; 68(1):92-8. · 2.82 Impact Factor
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ABSTRACT: A novel series of DL-galactan hybrids extracted from the red seaweed Gymnogongrus torulosus, was evaluated for its in vitro antiviral properties against herpes simplex virus type 2 (HSV-2) and dengue virus 2 (DEN-2). These compounds were very active against both viruses with inhibitory concentration 50% (IC50) values in the range 0.6-16 microg/ml for HSV-2 and 0.19-1.7 microg/ml for DEN-2, respectively, as determined in a virus plaque reduction assay in Vero cells. The DL-galactans lacked of cytotoxic effects, on stationary as well as on actively dividing cells, and anticoagulant properties. Some of the compounds showed a variable level of direct inactivating effect on both virions, with virucidal concentration 50% values exceeding the IC50s obtained by plaque reduction assay. Full inhibitory activity was achieved when the galactans were present during virus adsorption period, suggesting that the mode of action of these compounds is an interference in the binding of the surface envelope glycoprotein with the cell receptor.
Antiviral chemistry & chemotherapy 04/2002; 13(2):83-9.
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ABSTRACT: Four macrocyclic trichothecenes, roridin A, roridin E, verrucarin A and verrucarin J, produced by the hypocrealean epibiont of Baccharis coridifolia, were evaluated for their inhibitory activity against the arenavirus Junin (JUNV), the etiological agent of Argentine hemorrhagic fever. The trichothecenes achieved a dose-dependent inhibition of JUNV multiplication at concentrations not affecting cell viability. The 50 % inhibitory concentration (IC50) values determined by a virus yield inhibition assay were in the range 1.2 - 4.9 ng/ml. The most active compound was verrucarin J which reduced JUNV yield more than 2 log units and had a similar effect against the arenavirus Tacaribe. The trichothecenes lacked virucidal effects on JUNV virions. From time of addition and removal experiments, it can be concluded that verrucarin J inhibited a late stage in the replicative cycle of JUNV, after 5 h of adsorption.
Planta Medica 04/2002; 68(3):209-12. · 2.15 Impact Factor
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ABSTRACT: Two new trisulfated triterpene glycosides, liouvillosides A (1) and B (2), have been isolated from the Antarctic sea cucumber Staurocucumis liouvillei. Their structures have been elucidated by spectroscopic analysis (NMR and FABMS) and chemical transformations. Liouvillosides A (1) and B (2) are two new examples of a small number of trisulfated triterpene glycosides from sea cucumbers belonging to the family Cucumariidae. Both glycosides were found to be virucidal against herpes simplex virus type 1 (HSV-1) at concentrations below 10 microg/mL.
Journal of Natural Products 07/2001; 64(6):732-6. · 3.13 Impact Factor
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ABSTRACT: Sulfated polysaccharides exhibit many biological properties such as antiviral and anticoagulant activities. Herein, we report the antiviral activity of sulfated galactans extracted from the red sea-weed Bostrychia montagnei against herpes simplex virus types 1 (strain F and the thymidine kinase-deficient strains Field and B2006) and 2 (strain G). Two crude extracts obtained with cold and hot water as well as some fractions obtained by anion exchange chromatography, inhibited significantly the replication of the different strains of herpesviruses as determined by plaque reduction assays. The inhibitory effect of the compounds studied here took place only when they were added during the adsorption period. They were found to be highly selective antiviral substances, causing no impairment of Vero cell viability. Furthermore, they had no direct inactivating effect on virions by incubation in a virucidal assay. The antiviral activity could be correlated with the molecular weight and sulfate content of the polysaccharides. Although sulfated polysaccharides are generally endowed with anticoagulant properties, the results of the activated partial thromboplastin time and the thrombine time assays indicated that the natural sulfated polysaccharides from Bostrychia montagnei have very low anticoagulant activity, confirming that there is no relation between the antiviral and anticoagulant properties.
Phytomedicine 02/2001; 8(1):53-8. · 3.27 Impact Factor
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ABSTRACT: To study the functional involvement of cellular membrane properties on arenavirus infection, saturated fatty acids of variable chain length (C10-C18) were evaluated for their inhibitory activity against the multiplication of Junin virus (JUNV). The most active inhibitor was lauric acid (C12), which reduced virus yields of several attenuated and pathogenic strains of JUNV in a dose dependent manner, without affecting cell viability. Fatty acids with shorter or longer chain length had a reduced or negligible anti-JUNV activity. Lauric acid did not inactivate virion infectivity neither interacted with the cell to induce a state refractory to virus infection. From mechanistic studies, it can be concluded that lauric acid inhibited a late maturation stage in the replicative cycle of JUNV. Viral protein synthesis was not affected by the compound, but the expression of glycoproteins in the plasma membrane was diminished. A direct correlation between the inhibition of JUNV production and the stimulation of triacylglycerol cell content was demonstrated, and both lauric-acid induced effects were dependent on the continued presence of the fatty acid. Thus, the decreased insertion of viral glycoproteins into the plasma membrane, apparently due to the increased incorporation of triacylglycerols, seems to cause an inhibition of JUNV maturation and release.
Archives of Virology 02/2001; 146(4):777-90. · 2.11 Impact Factor
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ABSTRACT: Fifteen antiretroviral Zn-finger active compounds with diverse chemical structures, including azoic compounds, hydrazide derivatives, disulphide-based reagents and others were screened in vitro against Junin virus (JUNV), the aetiological agent of Argentine haemorrhagic fever, by a virus yield inhibition assay in Vero cells. Cytotoxicity was evaluated simultaneously by the MTT method. Of the compounds, three were totally inactive as antivirals, nine presented moderate anti JUNV-activity and three were truly active with EC50 (effective concentration 50%) values in the range 6.5-9.3 microM and with selectivity indices greater than 10. The most active inhibitors, named NSC20625, 3-7 and 2-71, demonstrated a broad range of action against arenaviruses, including several attenuated and pathogenic strains of JUNV as well as the antigenically related Tacaribe virus (TACV) and Pichinde virus (PICV). The direct treatment of JUNV and TACV virions with the compounds showed two types of behaviour: the aromatic disulphide NSC20625 was a very potent virucidal agent, whereas the other two compounds exhibited moderate or negligible virus-inactivating properties.
Antiviral chemistry & chemotherapy 06/2000; 11(3):231-7.
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ABSTRACT: Carrageenans extracted from cystocarpic and tetrasporic Stenogramme interrupta were analysed by chemical and spectroscopic methods. The carrageenan from cystocarpic plants is composed predominantly of 0.5 M KCl-insoluble and 1 M KCl-soluble fractions. The insoluble fraction contained iota-carrageenan as the major component with alpha-carrageenan and pyruvated carrageenan as minor components. The soluble fraction is highly heterogeneous and did not contain the precursors mu- and nu-carrageenans. The polysaccharide from tetrasporic plants is composed of zeta- and lambda-carrageenans, and low sulfated galactans. It is soluble in KCl and partly cyclized by alkaline treatment. The antiviral and anticoagulant properties of the insoluble polysaccharide fraction from cystocarpic S. interrupta and the polysaccharide from tetrasporic S. interrupta are reported the results of which suggest promising antiherpetic activity.
Phytochemistry 02/2000; 53(1):81-6. · 3.35 Impact Factor
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ABSTRACT: The lambda-carrageenan 1T1, the kappa/iota-carrageenan 1C1 and the mu/nu-type 1C3, isolated from the red seaweed Gigartina skottsbergii, proved to be potent and selective inhibitors of herpes simplex virus (HSV) types 1 and 2. The antiviral IC50 values determined by virus yield inhibition assay in different cell lines ranged from 0.4 to 3.3 microg/ml, and no cytotoxic effects, measured by trypan blue exclusion on stationary or proliferating cells, tetrazolium salt method or cell protein synthesis, were observed. Time of addition and attachment studies suggested that the main target for antiviral action of the three carrageenans was virus adsorption, whereas no effect on virus internalization, or early or late protein synthesis was detected. However, the lambda-carrageenan 1T1 was still significantly inhibitory when added any time after adsorption. The pretreatment of virions with the carrageenans showed that 1C1 and 1C3 lacked direct inactivating effect at concentrations near the antiviral IC50 but 1T1 exerted virucidal action. The cyclization of 1T1 to afford the derivative 1T1T1 maintained the antiviral activity but eliminated the virucidal properties. Thus, the structure of 1T1 seems to be responsible for its differential behavior from 1C1 and 1C3, probably allowing a more stable binding to HSV, leading to virion inactivation. In contrast, 1C1 and 1C3 fail to bind with high affinity to virus alone, but are able to interfere with the interaction between HSV particles and the cell.
Antiviral Research 10/1999; 43(2):93-102. · 4.30 Impact Factor
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ABSTRACT: Purine carbanucleosides built on a 6-oxabicyclo[3.1.0]hexane template were synthesized from readily available 2-cyclopentenone employing a Mitsunobu reaction to incorporate the base onto the carbocyclic ring. Both adenosine and guanosine analogues exhibited moderate antiviral activity.
Nucleosides & nucleotides 10/1999; 18(10):2219-31. · 1.13 Impact Factor
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ABSTRACT: The effects of two myristic acid analogs on Junin virus (JV) replication were investigated. The compounds chosen for the study were DL-2-hydroxymyristic acid (2OHM), an inhibitor of N-myristoyltransferase (NMT), which binds the enzyme and blocks protein myristoylation, and 13-oxamyristic acid (13OM), a competitive inhibitor of NMT which incorporates into the protein instead of myristic acid. Both types of analogs achieved dose-dependent inhibition of viral multiplication at concentrations not affecting cell viability. The 50% inhibitory concentration values determined by a virus-yield inhibition assay for different strains of JV, including a human pathogenic strain, and for the related arenavirus, Tacaribe, were in the range 1.6 to 20.1 microM, with 13OM as the most active compound. From time of addition and removal experiments, it can be concluded that both analogs inhibit a late stage in the JV replicative cycle, and their effect was partially reversible. The cytoplasmic and surface expression of JV glycoproteins was not affected in the presence of the compounds, as revealed by immunofluorescence staining, suggesting that JV glycoprotein myristoylation would not be essential for the intracellular transport of the envelope proteins, but it may have an important role in their interaction with the plasma membrane during virus budding.
Microbes and Infection 07/1999; 1(8):609-14. · 3.10 Impact Factor
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ABSTRACT: Disodium 3beta,21-dihydroxypregn-5-en-20-one disulfate (2), sodium 3beta,21-dihydroxypregn-5-en-20-one 3-sulfate (3), sodium 3beta,21-dihydroxypregn-5-en-20-one 21-sulfate (4), and disodium 3beta,6alpha-dihydroxy-5alpha-pregnan-20-one disulfate (6) have been synthesized and completely characterized for the first time from readily available materials. Sulfation was performed using triethylamine-sulfur trioxide complex in dimethylformamide as the sulfating agent. Selective sulfation of 3beta,21-dihydroxypregn-5-en-20-one rendered sodium 3beta,21-dihydroxypregn-5-en-20-one 3-sulfate (3) as the major compound. The synthetic sulfated steroids as well as natural disulfated polyhydroxysteroids (7-9) isolated by us from the antarctic ophiuroid Astrotoma agassizii and the synthetic derivatives disodium 2beta,3alpha,21-trihydroxy-(20R)-cholesta-5,24-diene 3-acetate, 2,21-disulfate (7a) and 2beta,3alpha,21-trihydroxy-(20R)-cholesta-5,24-diene (7b) were comparatively evaluated for their inhibitory effect on the replication of one DNA (HSV-2) and two RNA (PV-3, JV) viruses. In general, steroids with sulfate groups at C-21 and C-2 or C-3 were the most effective in their inhibitory action against HSV-2 and also proved to be active against PV-3 and JV.
Steroids 06/1999; 64(5):335-40. · 2.83 Impact Factor
