RESUMEN
Previously, we discovered geldanamycin, a ligand of heat shock protein 90, effectively inhibited herpes simplex virus type 1 replication in vitro and in vivo (mouse encephalitis model). In this study, we demonstrate that geldanamycin has very strong activities against herpes simplex virus type 2 in vitro and in vivo (mouse vagina model). In mouse vagina model, administration of geldanamycin suspension to vagina after virus infection protected the infected mice from death and increased the average survival days in a dose-dependent manner. Geldanamycin also significantly reduced virus shedding from mouse vagina. All geldanamycin-treated groups were statistically significant when compared with the infected control group. The high-dose group of geldanamycin (5.72 mg kg(-1)) was better than acyclovir group (2.86 mg kg(-1)). All geldanamycin vaginal administration mock-infected groups did not show significant body weight loss. Although geldanamycin has strong antiviral activities against various DNA and RNA viruses, geldanamycin is not suitable for systemic administration because of its high toxicity. We consider that geldanamycin is a candidate of topical usage for the treatment of herpes simplex virus type infections.
Asunto(s)
Antivirales/administración & dosificación , Antivirales/farmacología , Benzoquinonas/administración & dosificación , Benzoquinonas/farmacología , Herpes Genital/tratamiento farmacológico , Herpesvirus Humano 2/efectos de los fármacos , Lactamas Macrocíclicas/administración & dosificación , Lactamas Macrocíclicas/farmacología , Replicación Viral/efectos de los fármacos , Administración Intravaginal , Animales , Modelos Animales de Enfermedad , Femenino , Herpes Genital/virología , Herpesvirus Humano 2/fisiología , Ratones , Análisis de Supervivencia , Resultado del Tratamiento , Vagina/virología , Esparcimiento de VirusRESUMEN
In order to find antiviral compounds with novel structures, geldanamycin and lamivudine with different antiviral mechanisms were conjunctively synthesized to acquire a new compound TC-GM, and the antiviral activity of TC-GM was measured. The antiviral activity against HIV-1 was examined by p24 antigen ELISA kit. The activity against HBV was examined by dotblot. The activity against HSV and CoxB virus was examined by CPE. TC-GM exhibited broad-spectrum antiviral activities similarly like geldanamycin. TC-GM inhibited the replication of different viruses, including HIV-1, HBV, HSV 1 and 2, CoxB6. TC-GM showed more potent inhibitory activity against HIV-1 and HBV than other detected virus.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Antivirales/síntesis química , Benzoquinonas/síntesis química , Lactamas Macrocíclicas/síntesis química , Lamivudine/síntesis química , Replicación Viral/efectos de los fármacos , Animales , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Antivirales/química , Antivirales/farmacología , Benzoquinonas/química , Benzoquinonas/farmacología , Línea Celular Tumoral , Chlorocebus aethiops , Enterovirus Humano B/efectos de los fármacos , Enterovirus Humano B/fisiología , VIH-1/efectos de los fármacos , VIH-1/fisiología , Células Hep G2 , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/fisiología , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 1/fisiología , Herpesvirus Humano 2/efectos de los fármacos , Herpesvirus Humano 2/fisiología , Humanos , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacología , Lamivudine/química , Lamivudine/farmacología , Células de Riñón Canino Madin Darby , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/virología , Células VeroRESUMEN
The purpose of this study is to find out anti-HIV-1 reverse transcriptase (RT)/protease (PR) activity and inhibition of virus replication in cell cultures of novel coumarin analogs and determine their structure-activity relationship. Coumarin derivatives have been demonstrated to inhibit the activity of HIV-1 RT/PR in cell free system. It also shows inhibition effects to HIV-1 replication in cell culture. Based on the Chinese traditional pharmacological characteristics and protein three dimension computer aided design, analogs of tetracyclic dipyranocoumarin were synthesized from natural leading compounds. We studied the relationship of antiviral effects and chemical structures via HIV-1 PR/RT enzyme models and cell culture model system. Seven compounds were designed and tested. Several compounds showed anti-HIV-1 activity in varying degrees, especially V0201 showed much higher anti-HIV-1 activity with 3.56 and 0.78 micromol x L(-1) of IC50 against HIV-1 PR/RT and 0.036 micromol x L(-1) against HIV-1 replication in PBMC cultures. V0201 with a novel structure may be a new leading compound. These new compounds are valuable for development of new anti-HIV drugs in the future.
Asunto(s)
Fármacos Anti-VIH/farmacología , Leucocitos Mononucleares/metabolismo , Piranocumarinas/farmacología , Replicación Viral/efectos de los fármacos , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Células Cultivadas , Proteína p24 del Núcleo del VIH/metabolismo , Proteasa del VIH/metabolismo , Transcriptasa Inversa del VIH/metabolismo , VIH-1/fisiología , Humanos , Concentración 50 Inhibidora , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/virología , Piranocumarinas/síntesis química , Piranocumarinas/química , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-ActividadRESUMEN
BACKGROUND: Previous studies have suggested that geldanamycin (GA) inhibits the replication of several viruses in vitro. Here, we aimed to synthesize and evaluate the antiviral activity of 17-amino-17-demethoxygeldanamycin derivatives. METHODS: A series of 17-substituted and 17-,19-disubstituted GA derivatives were screened for antiviral activities against eight different viral strains, including herpesvirus, hepatitis virus, retrovirus and picornavirus. RESULTS: Most of the tested compounds showed inhibitory activity against the viruses and showed reduced cytotoxicity in vitro as compared with the parent compound GA. In vivo efficacy evaluation results showed that compound 6 noticeably inhibited duckling hepatitis B virus DNA replication in duckling serum after oral administration. Viral rebound did not occur after termination of the treatment. The modified GA derivatives also showed median lethal dose values that were higher than that of the parent GA in mice intraperitoneally treated with the study compounds. CONCLUSIONS: Targeting heat-shock protein 90 could be a new antiviral approach that is not prone to the development of drug resistance. The 17-amino-17-demethoxygeldanamycin derivatives could be novel agents with potential antiviral activity.
Asunto(s)
Antivirales/farmacología , Benzoquinonas/farmacología , Enterovirus Humano B/efectos de los fármacos , VIH-1/efectos de los fármacos , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Virus de Hepatitis/efectos de los fármacos , Herpesviridae/efectos de los fármacos , Lactamas Macrocíclicas/farmacología , Animales , Antivirales/síntesis química , Antivirales/toxicidad , Benzoquinonas/química , Benzoquinonas/toxicidad , Línea Celular Tumoral , Chlorocebus aethiops , Patos , Infecciones por Hepadnaviridae/tratamiento farmacológico , Infecciones por Hepadnaviridae/virología , Virus de la Hepatitis B del Pato/efectos de los fármacos , Virus de la Hepatitis B del Pato/fisiología , Humanos , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/toxicidad , Ratones , Pruebas de Sensibilidad Microbiana , Células Vero , Replicación Viral/efectos de los fármacosRESUMEN
Cycloheximide (CHX) inhibits protein synthesis in most eukaryotic cells and it is a well-known tool commonly used in biochemical research. In this paper, the antiviral spectrum of CHX against several DNA and RNA viruses have been evaluated. CHX showed strong inhibitory activities against several RNA viruses such as HIV-1, influenza viruses, coxsackie B virus, enterovirus (EV71) and several DNA viruses such as HSV and HCMV. Especially the strong inhibitory activities of CHX against coxsackie B virus and enterovirus caught our attention, since effective drugs available in clinic are limited. The SAR of CHX derivatives also has been discussed in the paper. The hydroxyl group at C-2' and carbonyl group at C-2" of CHX are essential for its antiviral activity. And modification to these groups results its derivatives' antiviral activities reduced or lost.
Asunto(s)
Antivirales , Cicloheximida , Virus ADN/efectos de los fármacos , Virus ARN/efectos de los fármacos , Antivirales/síntesis química , Antivirales/química , Antivirales/farmacología , Línea Celular , Cicloheximida/análogos & derivados , Cicloheximida/síntesis química , Cicloheximida/química , Cicloheximida/farmacología , Enterovirus/efectos de los fármacos , Enterovirus Humano B/efectos de los fármacos , HumanosAsunto(s)
Antivirales/síntesis química , Cicloheximida/análogos & derivados , Virus de la Hepatitis B/efectos de los fármacos , Piperidonas/síntesis química , Antivirales/química , Antivirales/farmacología , Cicloheximida/química , Cicloheximida/farmacología , Piperidonas/química , Piperidonas/farmacología , Difracción de Rayos XRESUMEN
Chlorogenic acid and its related compounds are abundant plant polyphenols that have a diverse antiviral activity. In this study, HepG2.2.15 cells and duck hepatitis B virus infection model were used as in vitro and in vivo models to evaluate their anti-HBV activity. In the cell model, all the three compounds inhibited HBV-DNA replication as well as HBsAg production. Chlorogenic acid and caffeic acid also reduced serum DHBV level in DHBV-infected duckling model. Moreover, the anti-HBV activity of crude extracts of coffee beans, which have a high content of chlorogenic acid, was studied. Both the extracts of regular coffee and that of decaffeinated coffee showed inhibitory effect on HBV replication.
Asunto(s)
Antivirales/uso terapéutico , Ácidos Cafeicos/farmacología , Ácido Clorogénico/uso terapéutico , Infecciones por Hepadnaviridae/tratamiento farmacológico , Virus de la Hepatitis B del Pato/efectos de los fármacos , Hepatitis Viral Animal/tratamiento farmacológico , Ácido Quínico/uso terapéutico , Animales , Antivirales/farmacología , Ácidos Cafeicos/uso terapéutico , Línea Celular , Ácido Clorogénico/farmacología , Patos , Hepatocitos/virología , Humanos , Concentración 50 Inhibidora , Ácido Quínico/farmacología , Suero/virología , Replicación Viral/efectos de los fármacosRESUMEN
An improved and practical synthesis of racemic 11-demethylcalanolide A [(+/-)-1] was developed. This improved process involved Pechmann reaction on phloroglucinol with ethyl butyrylacetate to give 5,7,-dihydroxy4-n-propylcoumarin (3). Poly phosphoric acid (PPA) catalyzed acylation of compound (3) with crotonic acid, then intramolecular cyclization was achieved simultaneously in one step to afford the key intermediate chromanone (4). A microwave assisted synthetic method preparing chromene (6) using chromenynation of chromanone (4) with 1, 1-diethoxy-methyl-2-butene was conducted. Luche reduction of chromene (6) using NaBH4 with CeCl3 x 7H2O preferably gave (+/-)-1. The overall yield of this four step synthesis of (+/-)-1 was around 32% increasing one fold more than that of the previous method. An in vitro investigation showed that (+/-)-1 exhibited inhibitory activities against both wild-type and drug-resistant HIV-1 in HIV-1 RT and cell culture assay, and significant synergistic effects in combination with AZT, T-20, and indinavir. Its LD50 of acute toxicity in mice by intragastric administration and by intraperitoneal injection were 735.65 mg kg(-1) and 525.10 mg x kg(-1), respectively. The Cmax and AUC(0-infinity) were 0.54 microg x mL(-1) and 1.08 (microg x mL(-1) x h, respectively. The dynamics study of the inhibition of mice sera on HIV-1 RT showed that mice treated with 100 mg x kg(-1 (+/-)-1 once intraperitoneally were similar to that of 5 mg x kg(-1) of known clinical effective anti-HIV-1 drug neverapine. The results suggested that further investigation of the anti-HIV candidate (+/-)-1 was warranted.
Asunto(s)
Transcriptasa Inversa del VIH/metabolismo , VIH-1/efectos de los fármacos , Piranocumarinas/síntesis química , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/inmunología , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/toxicidad , Sinergismo Farmacológico , VIH-1/enzimología , Humanos , Sueros Inmunes/farmacología , Indinavir/farmacología , Dosificación Letal Mediana , Masculino , Ratones , Piranocumarinas/inmunología , Piranocumarinas/farmacología , Piranocumarinas/toxicidad , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/inmunología , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/toxicidad , Zidovudina/farmacologíaRESUMEN
Geldanamycin (GA) is an antibiotic targeting the ADP/ATP binding site of heat shock protein 90 (Hsp90). In screening for anti-herpes simplex virus type 1 (HSV-1) candidates, we found GA active against HSV-1. HSV-1 replication in vitro was significantly inhibited by GA with an 50% inhibitory concentration of 0.093 microM and a concentration that inhibited cellular growth 50% in comparison with the results seen with untreated controls of 350 microM. The therapeutic index of GA was over 3700 (comparable to the results seen with acyclovir). GA did not inhibit HSV-1 thymidine kinase. Cells infected with HSV-1 demonstrated cell cycle arrest at the G(1)/S transition; however, treatment with GA resulted in a cell cycle distribution pattern identical to that of untreated cells, indicating a restoration of cell growth in HSV-1-infected cells by GA treatment. Accordingly, HSV-1 DNA synthesis was suppressed in HSV-1(+) cells treated with GA. The antiviral mechanism of GA appears to be associated with Hsp90 inactivation and cell cycle restoration, which indicates that GA exhibits broad-spectrum antiviral activity. Indeed, GA exhibited activities in vitro against other viruses, including severe acute respiratory syndrome coronavirus. Since GA inhibits HSV-1 through a cellular mechanism unique among HSV-1 agents, we consider it a new candidate agent for HSV-1.
Asunto(s)
Antivirales , Herpesvirus Humano 1/efectos de los fármacos , Quinonas/farmacología , Replicación Viral/efectos de los fármacos , Adsorción , Animales , Benzoquinonas , Southern Blotting , Ciclo Celular , Células Cultivadas , Chlorocebus aethiops , Inhibidores Enzimáticos/farmacología , Proteínas HSP90 de Choque Térmico/química , Herpesvirus Humano 1/genética , Lactamas Macrocíclicas , Ligandos , Inhibidores de la Síntesis del Ácido Nucleico , Plásmidos/genética , Timidina Quinasa/antagonistas & inhibidores , Células VeroRESUMEN
BACKGROUND: To determine the feasibility of inhibition of duck hepatitis B virus (DHBV) DNA replication by antisense phosphorothioate oligodeoxynucleotides corresponding to DHBV transcription region. METHODS: The authors designed three antisense phosphorothioate oligodeoxynucleotides which correspond to DHBV PreS1,PreS2 and S antigen gene promotors respectively. The DNA replication level was detected with Southern blot method and cpm calculation. RESULTS: Primary duck hepatocyte culture was treated with 1.5 micromol/L antisense oligodeoxynucleotides in vitro, all the antisense fragments caused a firm inhibition of viral DNA replication and the inhibition rates were 61.5%, 69.3% and 62.4%, respectively. In vivo, the animals were treated with 10 microgram/g PreS1 antigen gene promotor antisense oligodeoxynucleotides per day for 6 days and a very strong inhibition rate of 87.9% was obtained. CONCLUSIONS: The results demonstrated the potential clinical application of antisense phosphorothioate oligodeoxynucleotides in clinics.