RESUMEN
Silymarin flavonolignans are well-known agents that typically possess antioxidative, anti-inflammatory, and hepatoprotective functions. Recent studies have also documented the antiviral activities of silymarin and its derivatives against several viruses, including the flaviviruses (hepatitis C virus and dengue virus), togaviruses (Chikungunya virus and Mayaro virus), influenza virus, human immunodeficiency virus, and hepatitis B virus. This review will describe some of the latest preclinical and clinical studies detailing the antiviral profiles of silymarin and its derivatives, and discuss their relevance for antiviral drug development.
Asunto(s)
Antivirales/farmacología , Flavonolignanos/farmacología , Silimarina/farmacología , Antivirales/química , Virus Chikungunya/efectos de los fármacos , Virus del Dengue/efectos de los fármacos , Flavivirus/efectos de los fármacos , Flavonolignanos/química , VIH/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Silimarina/química , Togaviridae/efectos de los fármacosRESUMEN
The antibiotic cerulenin, an inhibitor of lipid synthesis, was shown to suppress Mayaro virus replication in Aedes albopictus cells at non-cytotoxic doses. Cerulenin blocked the incorporation of [3H]glycerol into lipids when present at any time post infection (p.i.). Cerulenin added at the beginning of infection inhibited the synthesis of virus proteins. However, when this antibiotic was added at later stages of infection, it had only a mild effect on the virus protein synthesis. The possibility that cerulenin acts by blocking an initial step in the Mayaro virus replication after virus entry and before late viral translation is discussed.
Asunto(s)
Antivirales/farmacología , Cerulenina/farmacología , Togaviridae/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Animales , Línea Celular/virología , Chlorocebus aethiops , Factores de Tiempo , Togaviridae/fisiología , Células VeroRESUMEN
The design, synthesis, and antiviral activities of 6'-homoneplanocin A (HNPA, 3) and its congeners having nucleobases other than adenine, such as 3-deazaadenine (4), guanine (5), thymine (6), and cytosine (7), were described. Starting from the known cyclopentenone derivative 8, the optically active (mesyloxy)cyclopentene derivative 15 was prepared, which was condensed with nucleobases then deprotected to give target compounds 3-7. Of these compounds, HNPA showed an antiviral activity spectrum that was comparable to, and an antiviral specificity that was higher than, that of neplanocin A. HNPA proved particularly active against human cytomegalovirus, vaccinia virus, parainfluenza virus, vesicular stomatitis virus, and arenaviruses, which is compatible with an antiviral action targeted at S-adenosylhomocysteine hydrolase. HNPA appears to be a promising candidate drug for the treatment of these viruses.
Asunto(s)
Adenosina/análogos & derivados , Antivirales/farmacología , Ciclopentanos/farmacología , Inhibidores Enzimáticos/farmacología , Hidrolasas/antagonistas & inhibidores , Adenosina/síntesis química , Adenosina/química , Adenosina/farmacología , Adenosilhomocisteinasa , Animales , Antivirales/síntesis química , Antivirales/química , Arenavirus del Nuevo Mundo/efectos de los fármacos , Bovinos , Chlorocebus aethiops , Ciclopentanos/síntesis química , Ciclopentanos/química , Citomegalovirus/efectos de los fármacos , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Fibroblastos/efectos de los fármacos , Células HeLa/efectos de los fármacos , Herpesviridae/efectos de los fármacos , Humanos , Estructura Molecular , Virus de la Parainfluenza 3 Humana/efectos de los fármacos , Picornaviridae/efectos de los fármacos , Conejos , Relación Estructura-Actividad , Togaviridae/efectos de los fármacos , Virus Vaccinia/efectos de los fármacos , Células Vero/efectos de los fármacos , Virus de la Estomatitis Vesicular Indiana/efectos de los fármacosRESUMEN
Guanine 7-N-oxide (G-7-Ox) was examined for its antiviral activity against 9 viruses based on plaque reduction, neuraminidase activity reduction, a fluorescent antibody technique or ELISA. The following viruses were included in the tests: influenza, Sendai, simian virus 5 (SV5), respiratory syncytial, western equine encephalitis, Japanese encephalitis, vesicular stomatitis, rabies and polio. G-7-Ox showed broad anti-RNA viral activity against all viruses tested, except for poliovirus. Inhibition of persistent SV5 infection by G-7-Ox indicates that its antiviral activity is independent of cytotoxicity.
Asunto(s)
Guanina/análogos & derivados , Virus ARN/efectos de los fármacos , Animales , Línea Celular , Ensayo de Inmunoadsorción Enzimática , Técnica del Anticuerpo Fluorescente , Guanina/farmacología , Guanina/fisiología , Virus de la Influenza A/efectos de los fármacos , Neuraminidasa/metabolismo , Paramyxoviridae/efectos de los fármacos , Poliovirus/efectos de los fármacos , ARN Viral/biosíntesis , Rhabdoviridae/efectos de los fármacos , Togaviridae/efectos de los fármacos , Ensayo de Placa Viral , Replicación Viral/efectos de los fármacosAsunto(s)
Encefalitis por Arbovirus/tratamiento farmacológico , Fiebres Hemorrágicas Virales/tratamiento farmacológico , Animales , Arenaviridae/efectos de los fármacos , Cricetinae , Encefalitis por Arbovirus/mortalidad , Fiebres Hemorrágicas Virales/mortalidad , Humanos , Ratones , Rhabdoviridae/efectos de los fármacos , Ribavirina/uso terapéutico , Togaviridae/efectos de los fármacosRESUMEN
A number of 5-substituted imidazole-4-carboxamide ribonucleosides were prepared and tested for their biological activity. Treatment of 5-chloro-1-beta-D-ribofuranosylimidazole-4-carboxamide (2) with methanethiol provided 5-(methylthio)-1-beta-D-ribofuranosylimidazole-4-carboxamide (3a). Similar treatment of 2 with ethanethiol or benzenemethanethiol gave the corresponding 5-ethylthio and 5-benzylthio derivatives 3b and 3c. Oxidation of 3a and 3b with m-chloroperoxybenzoic acid furnished the corresponding sulfonyl derivatives 4a and 4b. Reductive cleavage of 3c with sodium naphthalene or Na/NH3 gave 5-mercapto-1-beta-D-ribofuranosylimidazole-4-carboxamide (5-thiobredinin, 5). Direct treatment of 2 with sodium hydrosulfide provided an alternate route to 5, the structure of which was established by single-crystal X-ray analysis. 5-Thiobredinin has a zwitterionic structure similar to that of bredinin. Glycosylation of persilylated ethyl 5(4)-methylimidazole-4(5)-carboxylate (6) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose in the presence of SnCl4 provided a quantitative yield of the corresponding tri-O-benzoyl nucleoside 7. Debenzoylation of 7 with MeOH/NH3 at ambient temperature gave ethyl 5-methyl-1-beta-D-ribofuranosylimidazole-4-carboxylate (8). Further ammonolysis of 8 or 7 at elevated temperature and pressure gave 5-methyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (9). All of these ribonucleosides were tested in Vero cell cultures and in mice against certain viruses. Compounds 3a and 3c exhibited significant activity against vaccinia virus in vitro, whereas 4a was effective against Rift Valley fever virus in mice. 5-Thiobredinin failed to exhibit appreciable antiviral or cytostatic activity (against L1210 and P388) in cell culture.
Asunto(s)
Aminoimidazol Carboxamida/uso terapéutico , Imidazoles/uso terapéutico , Ribonucleósidos/uso terapéutico , Virus/efectos de los fármacos , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/síntesis química , Aminoimidazol Carboxamida/farmacología , Animales , Fenómenos Químicos , Química , Leucemia L1210/tratamiento farmacológico , Leucemia P388/tratamiento farmacológico , Ratones , Virus de la Parainfluenza 3 Humana/efectos de los fármacos , Ribavirina/farmacología , Ribonucleósidos/síntesis química , Ribonucleósidos/farmacología , Virus de la Fiebre del Valle del Rift/efectos de los fármacos , Simplexvirus/efectos de los fármacos , Togaviridae/efectos de los fármacos , Virus Vaccinia/efectos de los fármacos , Difracción de Rayos XRESUMEN
Binary combinations of the N-nucleoside ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) and the C-nucleoside analog selenazofurin (2-beta-D-ribofuranosylselenazole-4-carboxamide) or tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) were tested in vitro for activity against Venezuelan equine encephalomyelitis, Japanese encephalitis, yellow fever, Rift Valley fever, Korean hemorrhagic fever, and Pichinde viruses. The 50% effective dose for each compound alone or in a series of combinations was determined with a plaque reduction assay. Combinations of ribavirin and selenazofurin were synergistic against Venezuelan equine encephalomyelitis, Japanese encephalitis, yellow fever, and Pichinde viruses, with fractional inhibitory concentrations of 0.1, 0.2, 0.4, 0.4, respectively, but showed additive effects against Korean hemorrhagic fever and Rift Valley fever viruses. Combinations of ribavirin and tiazofurin were synergistic against yellow fever and Japanese encephalitis (fractional inhibitory concentrations, 0.41 and 0.48, respectively) but showed additive effects against Korean hemorrhagic fever virus. Combinations of selenazofurin and tiazofurin had additive effects against Japanese encephalitis, yellow fever, and Korean hemorrhagic fever viruses. The effect of combinations on cell toxicity was additive, both in monolayers of nondividing cells incubated under agar for the same period as the plaque assay and for rapidly dividing cells given short-term exposure (4 h), followed by determination of the proportion of surviving cells with a colony forming assay.
Asunto(s)
Antivirales/farmacología , Arenaviridae/efectos de los fármacos , Bunyaviridae/efectos de los fármacos , Compuestos de Organoselenio , Ribavirina/farmacología , Ribonucleósidos/farmacología , Selenio/farmacología , Togaviridae/efectos de los fármacos , Antivirales/toxicidad , Combinación de Medicamentos , Sinergismo Farmacológico , IMP Deshidrogenasa/antagonistas & inhibidores , Ribavirina/análogos & derivadosRESUMEN
The behaviour of cell cultures from 11 to 18 days-old Swiss albino mouse embryo infected with Pixuna virus was studied. Eleven day-old embryo cultures showed to be a permissive system supporting a productive and cytocidal infection. In contrast, the 13 to 18 day-old embryo cultures were also permissive and productive but no evidence of cytopathic effect was observed. D-glucosamine did not affect the infectivity titer of the Pixuna virus when 11 day-old embryo cultures were used. In these cultures the eclipse phase was observed between 15 and 90 min post-absorption (Figure 1).
Asunto(s)
Togaviridae/crecimiento & desarrollo , Animales , Efecto Citopatogénico Viral , Glucosamina/farmacología , Técnicas de Cultivo de Órganos , Ratas/embriología , Togaviridae/efectos de los fármacos , Cultivo de Virus/métodos , Replicación Viral/efectos de los fármacosRESUMEN
Brain fractions isolated from Swiss albino mice were studied from the physical, chemical and biological viewpoints. The isoionic point gave a value of 4.16 +/- 0.17 indicating the presence of acid groups. UV absorption experiments showed an opening of the structure when the fractions were heated. The presence of neuraminic acid group was demonstrated using o-phenanthroline and, when heated, the structure exposed the hidden neuraminic acid. The biological property of inhibiting viral hemagglutination increased when the fractions were heated. EEE virus was used as hemagglutinating antigen. The treatment with alpha-chymotrypsin destroyed the inhibiting viral hemagglutination property in 120 seconds. Polyacrylamide gel electrophoresis showed that the fractions are proteic in nature. Glyco- and lipoproteins were only present in the fraction with the inhibitory property. Only neutral lipids were demonstrated.
Asunto(s)
Química Encefálica , Hemaglutinación por Virus/efectos de los fármacos , Togaviridae/efectos de los fármacos , Animales , Depresión Química , Glicoproteínas/aislamiento & purificación , Glicoproteínas/farmacología , Lipoproteínas/aislamiento & purificación , Lipoproteínas/farmacología , Ratones , Proteínas del Tejido Nervioso/aislamiento & purificación , Proteínas del Tejido Nervioso/farmacología , Extractos de Tejidos , Togaviridae/fisiologíaRESUMEN
Unsaturated free fatty acids such as oleic, arachidonic or linoleic at concentrations of 5-25 microgram/ml inactivate enveloped viruses such as herpes, influenza, Sendai, Sindbis within minutes of contact. At these concentrations the fatty acids are inocuous to animal host cells in vitro. Naked viruses, such as polio, SV40 or EMC are not affected by these acids. Saturated stearic acid does not inactivate any viruses at concentrations tested. Though the mode of action of unsaturated fatty acids is not understood, electronmicrographs of enveloped viruses treated by them indicate that the inactivation is associated with disintegration of the virus envelope.