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1.
Brief Bioinform ; 23(1)2022 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-34962256

RESUMEN

The pharmacological arsenal against the COVID-19 pandemic is largely based on generic anti-inflammatory strategies or poorly scalable solutions. Moreover, as the ongoing vaccination campaign is rolling slower than wished, affordable and effective therapeutics are needed. To this end, there is increasing attention toward computational methods for drug repositioning and de novo drug design. Here, multiple data-driven computational approaches are systematically integrated to perform a virtual screening and prioritize candidate drugs for the treatment of COVID-19. From the list of prioritized drugs, a subset of representative candidates to test in human cells is selected. Two compounds, 7-hydroxystaurosporine and bafetinib, show synergistic antiviral effects in vitro and strongly inhibit viral-induced syncytia formation. Moreover, since existing drug repositioning methods provide limited usable information for de novo drug design, the relevant chemical substructures of the identified drugs are extracted to provide a chemical vocabulary that may help to design new effective drugs.


Asunto(s)
Antivirales/farmacología , Tratamiento Farmacológico de COVID-19 , COVID-19 , Células Gigantes , Pirimidinas/farmacología , SARS-CoV-2/metabolismo , Estaurosporina/análogos & derivados , Células A549 , COVID-19/metabolismo , Biología Computacional , Evaluación Preclínica de Medicamentos , Reposicionamiento de Medicamentos , Células Gigantes/metabolismo , Células Gigantes/virología , Humanos , Estaurosporina/farmacología
2.
Nature ; 594(7861): 88-93, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33827113

RESUMEN

COVID-19 is a disease with unique characteristics that include lung thrombosis1, frequent diarrhoea2, abnormal activation of the inflammatory response3 and rapid deterioration of lung function consistent with alveolar oedema4. The pathological substrate for these findings remains unknown. Here we show that the lungs of patients with COVID-19 contain infected pneumocytes with abnormal morphology and frequent multinucleation. The generation of these syncytia results from activation of the SARS-CoV-2 spike protein at the cell plasma membrane level. On the basis of these observations, we performed two high-content microscopy-based screenings with more than 3,000 approved drugs to search for inhibitors of spike-driven syncytia. We converged on the identification of 83 drugs that inhibited spike-mediated cell fusion, several of which belonged to defined pharmacological classes. We focused our attention on effective drugs that also protected against virus replication and associated cytopathicity. One of the most effective molecules was the antihelminthic drug niclosamide, which markedly blunted calcium oscillations and membrane conductance in spike-expressing cells by suppressing the activity of TMEM16F (also known as anoctamin 6), a calcium-activated ion channel and scramblase that is responsible for exposure of phosphatidylserine on the cell surface. These findings suggest a potential mechanism for COVID-19 disease pathogenesis and support the repurposing of niclosamide for therapy.


Asunto(s)
Anoctaminas/antagonistas & inhibidores , COVID-19/patología , Fusión Celular , Evaluación Preclínica de Medicamentos , Células Gigantes/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , Glicoproteína de la Espiga del Coronavirus/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/patología , Células Epiteliales Alveolares/virología , Animales , Anoctaminas/metabolismo , COVID-19/metabolismo , COVID-19/virología , Señalización del Calcio/efectos de los fármacos , Línea Celular , Canales de Cloruro/metabolismo , Chlorocebus aethiops , Femenino , Células Gigantes/metabolismo , Células Gigantes/virología , Humanos , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/virología , Masculino , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidad , Glicoproteína de la Espiga del Coronavirus/metabolismo , Replicación Viral/efectos de los fármacos
3.
Viruses ; 10(7)2018 07 11.
Artículo en Inglés | MEDLINE | ID: mdl-29997331

RESUMEN

The baculovirus-insect cell expression system has been widely used for heterologous protein expression and virus-like particles (VLPs) expression. In this study, we established a new method for antiviral screening targeting to glycoprotein E of flaviviruses based on the baculovirus expression system. ZIKV is a mosquito-borne flavivirus and has posed great threat to the public health. It has been reported that ZIKV infection was associated with microcephaly and serious neurological complications. Our study showed that either ZIKV E or prME protein expressed in insect cells can form VLPs and induce membrane fusion between insect cells. Therefore, the E protein, which is responsible for receptor binding, attachment, and virus fusion during viral entry, achieved proper folding and retained its fusogenic ability in VLPs when expressed in this system. The syncytia in insect cells were significantly reduced by the anti-ZIKV-E specific polyclonal antibody in a dose-dependent manner. AMS, a thiol-conjugating reagent, was also shown to have an inhibitory effect on the E protein induced syncytia and inhibited ZIKV infection by blocking viral entry. Indeed the phenomenon of syncytial formation induced by E protein expressed VLPs in insect cells is common among flaviviruses, including Japanese encephalitis virus (JEV), Dengue virus type 2 (DENV-2), and tick-borne encephalitis virus (TBEV). This inhibition effect on syncytial formation can be developed as a novel, safe, and simple antiviral screening approach for inhibitory antibodies, peptides, or small molecules targeting to E protein of ZIKV and other flaviviruses.


Asunto(s)
Baculoviridae/genética , Infecciones por Flavivirus/virología , Flavivirus/fisiología , Expresión Génica , Vectores Genéticos/genética , Células Gigantes/virología , Animales , Antivirales/farmacología , Línea Celular , Evaluación Preclínica de Medicamentos , Flavivirus/efectos de los fármacos , Flavivirus/ultraestructura , Ingeniería Genética , Humanos , Transporte de Proteínas , Ensayo de Placa Viral , Proteínas Virales/metabolismo , Internalización del Virus/efectos de los fármacos
4.
J Virol ; 88(11): 6137-47, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24648446

RESUMEN

UNLABELLED: Orthoreovirus fusion-associated small transmembrane (FAST) proteins are dedicated cell-cell fusogens responsible for multinucleated syncytium formation and are virulence determinants of the fusogenic reoviruses. While numerous studies on the FAST proteins and enveloped-virus fusogens have delineated steps involved in membrane fusion and pore formation, little is known about the mechanics of pore expansion needed for syncytiogenesis. We now report that RNA interference (RNAi) knockdown of annexin A1 (AX1) expression dramatically reduced both reptilian reovirus p14 and measles virus F and H protein-mediated pore expansion during syncytiogenesis but had no effect on pore formation. A similar effect was obtained by chelating intracellular calcium, which dramatically decreased syncytiogenesis in the absence of detectable effects on p14-induced pore formation. Coimmunoprecipitation revealed calcium-dependent interaction between AX1 and p14 or measles virus F and H proteins, and fluorescence resonance energy transfer (FRET) demonstrated calcium-dependent p14-AX1 interactions in cellulo. Furthermore, antibody inhibition of extracellular AX1 had no effect on p14-induced syncytium formation but did impair cell-cell fusion mediated by the endogenous muscle cell fusion machinery in C2C12 mouse myoblasts. AX1 can therefore exert diverse, fusogen-specific effects on cell-cell fusion, functioning as an extracellular mediator of differentiation-dependent membrane fusion or as an intracellular promoter of postfusion pore expansion and syncytium formation following virus-mediated cell-cell fusion. IMPORTANCE: Numerous enveloped viruses and nonenveloped fusogenic orthoreoviruses encode membrane fusion proteins that induce syncytium formation, which has been linked to viral pathogenicity. Considerable insights into the mechanisms of membrane fusion have been obtained, but processes that drive postfusion expansion of fusion pores to generate syncytia are poorly understood. This study identifies intracellular calcium and annexin A1 (AX1) as key factors required for efficient pore expansion during syncytium formation mediated by the reptilian reovirus p14 and measles virus F and H fusion protein complexes. Involvement of intracellular AX1 in syncytiogenesis directly correlates with a requirement for intracellular calcium in p14-AX1 interactions and pore expansion but not membrane fusion and pore formation. This is the first demonstration that intracellular AX1 is involved in pore expansion, which suggests that the AX1 pathway may be a common host cell response needed to resolve virus-induced cell-cell fusion pores.


Asunto(s)
Anexina A1/metabolismo , Calcio/metabolismo , Regulación Viral de la Expresión Génica/genética , Células Gigantes/virología , Virus del Sarampión/metabolismo , Orthoreovirus/metabolismo , Proteínas Virales/metabolismo , Animales , Fusión Celular , Línea Celular , Chlorocebus aethiops , ADN Complementario/genética , Fibroblastos , Transferencia Resonante de Energía de Fluorescencia , Regulación Viral de la Expresión Génica/fisiología , Células Gigantes/fisiología , Proteínas Fluorescentes Verdes , Humanos , Ratones , Orthoreovirus/patogenicidad , Plásmidos/genética , Codorniz , Interferencia de ARN , Células Vero , Proteínas Virales de Fusión/metabolismo , Virulencia
5.
Arch Pharm Res ; 33(6): 863-6, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20607490
6.
Phytother Res ; 24(8): 1132-40, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20041417

RESUMEN

Herpes simplex virus type 1 (HSV-1) causes significant health problems from periodical skin and corneal lesions to encephalitis. We report here that an aqueous extract preparation from the barks of neem plant Azardirachta indica acts as a potent entry inhibitor against HSV-1 infection into natural target cells. The neem bark extract (NBE) significantly blocked HSV-1 entry into cells at concentrations ranging from 50 to 100 microg/ml. The blocking activity of NBE was observed when the extract was pre-incubated with the virus but not with the target cells, suggesting a direct antiHSV-1 property of the neem bark. Further, virions treated with NBE failed to bind the cells which implicate a role of NBE as an attachment step blocker. Cells treated with NBE also inhibited HSV-1 glycoprotein-mediated cell-cell fusion and polykaryocytes formation suggesting an additional role of NBE at the viral fusion step. These findings open a potential new avenue for the development of NBE as a novel antiherpetic microbicide.


Asunto(s)
Antivirales/farmacología , Azadirachta/química , Herpesvirus Humano 1/efectos de los fármacos , Extractos Vegetales/farmacología , Animales , Células CHO , Fusión Celular , Chlorocebus aethiops , Cricetinae , Cricetulus , Fibroblastos , Células Gigantes/efectos de los fármacos , Células Gigantes/virología , Herpesvirus Humano 1/fisiología , Humanos , Corteza de la Planta/química , Células Vero , Proteínas del Envoltorio Viral/metabolismo , Internalización del Virus/efectos de los fármacos
7.
BMC Complement Altern Med ; 9: 29, 2009 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-19656383

RESUMEN

BACKGROUND: Highly active anti-retroviral therapy (HAART) is the current HIV/AIDS treatment modality. Despite the fact that HAART is very effective in suppressing HIV-1 replication and reducing the mortality of HIV/AIDS patients, it has become increasingly clear that HAART does not offer an ultimate cure to HIV/AIDS. The high cost of the HAART regimen has impeded its delivery to over 90% of the HIV/AIDS population in the world. This reality has urgently called for the need to develop inexpensive alternative anti-HIV/AIDS therapy. This need has further manifested by recent clinical trial failures in anti-HIV-1 vaccines and microbicides. In the current study, we characterized a panel of extracts of traditional Chinese medicinal herbal plants for their activities against HIV-1 replication. METHODS: Crude and fractionated extracts were prepared from various parts of nine traditional Chinese medicinal herbal plants in Hainan Island, China. These extracts were first screened for their anti-HIV activity and cytotoxicity in human CD4+ Jurkat cells. Then, a single-round pseudotyped HIV-luciferase reporter virus system (HIV-Luc) was used to identify potential anti-HIV mechanisms of these extracts. RESULTS: Two extracts, one from Euphorbiaceae, Trigonostema xyphophylloides (TXE) and one from Dipterocarpaceae, Vatica astrotricha (VAD) inhibited HIV-1 replication and syncytia formation in CD4+ Jurkat cells, and had little adverse effects on host cell proliferation and survival. TXE and VAD did not show any direct inhibitory effects on the HIV-1 RT enzymatic activity. Treatment of these two extracts during the infection significantly blocked infection of the reporter virus. However, pre-treatment of the reporter virus with the extracts and treatment of the extracts post-infection had little effects on the infectivity or gene expression of the reporter virus. CONCLUSION: These results demonstrate that TXE and VAD inhibit HIV-1 replication likely by blocking HIV-1 interaction with target cells, i.e., the interaction between gp120 and CD4/CCR5 or gp120 and CD4/CXCR4 and point to the potential of developing these two extracts to be HIV-1 entry inhibitors.


Asunto(s)
Fármacos Anti-VIH/farmacología , Dipterocarpaceae , Euphorbiaceae , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Extractos Vegetales/farmacología , Replicación Viral/efectos de los fármacos , Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD4-Positivos/efectos de los fármacos , Línea Celular Tumoral , Células Gigantes/efectos de los fármacos , Células Gigantes/virología , Infecciones por VIH/virología , VIH-1/fisiología , Humanos , Células Jurkat
8.
J Ethnopharmacol ; 98(3): 323-7, 2005 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-15814267

RESUMEN

Parietaria diffusa M. et K., Urtica dioica L. (Urticaceae) and Sambucus nigra L. (Caprifoliaceae) are plants usually used in popular medicine of central Italy for treating numerous diseases, first of all Herpes zoster. Several plant products have been described as potential antiviral agents, with special attention being devoted to those having retroviruses as etiological agents, including acquired immunodeficiency syndrome (AIDS), in which a retrovirus, the designated human immunodeficiency virus HIV, has been clearly identified as the primary cause of this disease. The present study proposes a preliminary screening of the antiviral activity of Parietaria diffusa, Sambucus nigra and Urtica dioica preparation against the feline immunodeficiency virus (FIV) infection. The feline immunodeficiency virus is a widespread lentivirus of domestic cats sharing numerous biological and pathogenic features with the human immunodeficiency virus (HIV). FIV infection in cats has therefore been proposed as an animal model for AIDS studies with respect to pathogenesis, chemotherapy, and vaccine development [Pedersen, N.C., 1993. Feline immunodeficiency virus infection. In: Levy, J.A. (Ed.), The Retroviridae. Plenum Press, New York; Bendinelli, M., Pistello, M., Lombardi, S., Poli, A., Garzelli, C., Matteucci, D., Ceccherini-Nelli, L., Malvaldi, G., Tozzini, F., 1995. Feline immunodeficiency virus: an interesting model for AIDS studies and an important cat pathogen. Clinical Microbiology Revue 8, 87-112; North, T.W., LaCasse, R.A., 1995. Testing anti-HIV drugs in the FIV model. Nature Medicine 1, 410-411; Matteucci, D., Pistello, M., Mazzetti, P., Giannechini, S., Isola, P., Merico, A., Zaccaro, L., Rizzati, A., Bendinelli, M., 2000. AIDS vaccination studies using feline immunodeficiency virus as a model: immunisation with inactivated whole virus suppresses viraemia levels following intravaginal challenge with infected cells but non-following intravenous challenge with cell-free virus. Vaccine 18, 119-130]. Early studies showed that some of them presented antiviral activity against infection of FIV as assayed by syncytia formation using feline kidney Crandell cells (CrFK).


Asunto(s)
Antivirales/farmacología , Etnobotánica , Virus de la Inmunodeficiencia Felina/efectos de los fármacos , Parietaria , Extractos Vegetales/farmacología , Sambucus nigra , Urtica dioica , Replicación Viral/efectos de los fármacos , Animales , Antivirales/aislamiento & purificación , Gatos , Células Cultivadas , Modelos Animales de Enfermedad , Células Gigantes/efectos de los fármacos , Células Gigantes/virología , Virus de la Inmunodeficiencia Felina/fisiología , Italia , Riñón/efectos de los fármacos , Riñón/virología
9.
Antimicrob Agents Chemother ; 48(10): 3858-70, 2004 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-15388446

RESUMEN

The plant lectins derived from Galanthus nivalis (Snowdrop) (GNA) and Hippeastrum hybrid (Amaryllis) (HHA) selectively inhibited a wide variety of human immunodeficiency virus type 1 (HIV-1) and HIV-2 strains and clinical (CXCR4- and CCR5-using) isolates in different cell types. They also efficiently inhibited infection of T lymphocytes by a variety of mutant virus strains. GNA and HHA markedly prevented syncytium formation between persistently infected HUT-78/HIV cells and uninfected T lymphocytes. The plant lectins did not measurably affect the antiviral activity of other clinically approved anti-HIV drugs used in the clinic when combined with these drugs. Short exposure of the lectins to cell-free virus particles or persistently HIV-infected HUT-78 cells markedly decreased HIV infectivity and increased the protective (microbicidal) activity of the plant lectins. Flow cytometric analysis and monoclonal antibody binding studies and a PCR-based assay revealed that GNA and HHA do not interfere with CD4, CXCR4, CCR5, and DC-SIGN and do not specifically bind with the membrane of uninfected cells. Instead, GNA and HHA likely interrupt the virus entry process by interfering with the virus envelope glycoprotein. HHA and GNA are odorless, colorless, and tasteless, and they are not cytotoxic, antimetabolically active, or mitogenic to human primary T lymphocytes at concentrations that exceed their antivirally active concentrations by 2 to 3 orders of magnitude. GNA and HHA proved stable at high temperature (50 degrees C) and low pH (5.0) for prolonged time periods and can be easily formulated in gel preparations for microbicidal use; they did not agglutinate human erythrocytes and were not toxic to mice when administered intravenously.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Galanthus/química , VIH-1/efectos de los fármacos , Liliaceae/química , Manosa/uso terapéutico , Aglutininas/farmacología , Animales , Fármacos Anti-VIH/química , Anticuerpos Monoclonales/química , Señalización del Calcio , División Celular/efectos de los fármacos , Sistema Libre de Células , Células Cultivadas , Técnicas de Cocultivo , Eritrocitos/efectos de los fármacos , Citometría de Flujo , Geles , Células Gigantes/citología , Células Gigantes/virología , VIH-1/genética , VIH-1/crecimiento & desarrollo , Humanos , Lectinas/uso terapéutico , Manosa/química , Ratones , Mitógenos/farmacología , Conejos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Temperatura
10.
Cancer Res ; 60(22): 6396-402, 2000 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-11103804

RESUMEN

Viral fusogenic membrane glycoproteins (FMGs) are candidates for gene therapy of solid tumors because they cause cell fusion, leading to formation of lethal multinucleated syncytia. However, the cellular mechanisms mediating cell death after FMG-induced cell fusion remain unclear. The present study was designed to examine the mechanisms by which FMG expression in hepatocellular carcinoma cells lead to cell death. Transfection of Hep3B cells with the Gibbon Ape leukemia virus hyperfusogenic envelope protein (GALV-FMG) resulted in the formation of multinucleated syncytia that reached a maximum 5 days after transfection (100 nuclei/syncytia). The syncytia were viable for a period of 2 days and then rapidly lost viability by day 5. Mitochondrial dysfunction occurred in GALV-FMG-induced syncytia prior to loss of viability with loss of the mitochondrial membrane potential, cellular ATP depletion, and release of mitochondrial cytochrome c-GFP into the cytosol. The pan-caspase inhibitor, Z-VAD-fmk, did not prevent cell death. However, glycolytic generation of ATP with fructose effectively increased cellular ATP and preserved syncytial viability. These data suggest that expression of FMG in hepatoma cells results in the formation of multinucleated syncytia, causing mitochondrial failure with ATP depletion, a bioenergetic form of cell death with necrosis. This form of cell death should be effective in vivo and enhance the bystander effect, suggesting that FMG-based gene therapy deserves further study for the treatment of hepatocellular and other cancers.


Asunto(s)
Carcinoma Hepatocelular/terapia , Terapia Genética/métodos , Células Gigantes/patología , Virus de la Leucemia del Gibón/genética , Neoplasias Hepáticas/terapia , Proteínas Virales de Fusión/genética , Adenosina Trifosfato/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Inhibidores de Caspasas , Caspasas/metabolismo , Muerte Celular/fisiología , Fusión Celular/métodos , Metabolismo Energético/fisiología , Fructosa/farmacología , Células Gigantes/metabolismo , Células Gigantes/virología , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Mitocondrias Hepáticas/metabolismo , Mitocondrias Hepáticas/fisiología , Necrosis , Fosforilación Oxidativa , Células Tumorales Cultivadas , Proteínas Virales de Fusión/biosíntesis
11.
Acta Pharmacol Sin ; 21(2): 179-82, 2000 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11263268

RESUMEN

AIM: To determine whether trichobitacin, a novel ribosome-inactivating protein purified from the root tubers of Trichosanthes kirilowii, possesses the anti-HIV activity. METHODS: The inhibition of syncytial cell formation induced by human immunodeficiency virus type 1 (HIV-1) was determined under microscope, reduction of HIV-1 p24 antigen expression level was measured by ELISA, and decrease in numbers of HIV-1 antigen positive cells in acutely and chronically infected cultures were detected by indirect immunofluorescence assay. RESULTS: Trichobitacin was found to greatly suppress syncytial cell formation induced by HIV-1 and to markedly reduce both expression of HIV-1 p24 antigen and the number of HIV antigen positive cells in acutely but not chronically HIV-1 infected culture. The median inhibitory concentration (IC50) in inhibition of syncytial cell formation and HIV antigen positive cells were 5 micrograms.L-1 (95% confidence limits: 1.3-20 micrograms.L-1) and 0.09 mg.L-1 (95% confidence limits: 0.011-0.755 mg.L-1), respectively. CONCLUSION: Trichobitacin is a novel ribosome-inactivating protein with anti-HIV-1 activity.


Asunto(s)
Fármacos Anti-VIH/farmacología , Proteína p24 del Núcleo del VIH/metabolismo , VIH-1/fisiología , Proteínas de Plantas/farmacología , Fármacos Anti-VIH/aislamiento & purificación , División Celular/efectos de los fármacos , Línea Celular , Cucurbitaceae/química , Medicamentos Herbarios Chinos/química , Células Gigantes/citología , Células Gigantes/virología , Humanos , Proteínas de Plantas/aislamiento & purificación , Proteínas Ribosómicas/efectos de los fármacos , Replicación Viral
12.
Phytother Res ; 13(3): 245-7, 1999 May.
Artículo en Inglés | MEDLINE | ID: mdl-10353170

RESUMEN

A crude extract of Caulerpa taxifolia was tested for its antiviral activity. The chloroform-methanol residue showed an interesting inhibitor effect in vitro toward the feline immunodeficiency virus (FIV), a valid model for studying the acquired immunodeficiency syndrome. This extract reduced the virus-induced syncytia in the cultured cells, the viral reverse transcriptase activity and the viral capsid protein P24 expression.


Asunto(s)
Antivirales/farmacología , Chlorophyta/química , Virus de la Inmunodeficiencia Felina/efectos de los fármacos , Extractos Vegetales/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Animales , Gatos , Línea Celular , Productos del Gen gag/metabolismo , Células Gigantes/virología , VIH-1/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Modelos Biológicos
13.
Antiviral Res ; 44(2): 113-22, 1999 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-10669261

RESUMEN

A polysaccharide extracted from the leaf of Rhizophora apiculata (RAP) was assessed in cell culture systems, for its activity against human and simian immunodeficiency viruses. RAP inhibited HIV-1 or HIV-2 or SIV strains in various cell cultures and assay systems. It blocked the expression of HIV-1 antigen in MT-4 cells and abolished the production of HIV-1 p24 antigen in peripheral blood mononuclear cells (PBMC); the 50% effective concentration (EC50) of RAP in HIV-1 infected MT-4 cells and in PBMC was 10.7 and 25.9 microg/ml, respectively. RAP (100 microg/ml) completely blocked the binding of HIV-1 virions to MT-4 cells. RAP also reduced the production of viral mRNA when added before virus adsorption. RAP inhibited syncytium formation in cocultures of MOLT-4 cells and MOLT-4/HIV-1(IIIB) cells. RAP did not prolong activated partial thromboplastin time (APTT) up to 500 microg/ml. These properties may be advantageous should RAP be considered for further development.


Asunto(s)
Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , VIH-2/efectos de los fármacos , Rosales/química , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Fármacos Anti-VIH/aislamiento & purificación , Anticoagulantes/aislamiento & purificación , Anticoagulantes/farmacología , Células Cultivadas , Efecto Citopatogénico Viral/efectos de los fármacos , Células Gigantes/efectos de los fármacos , Células Gigantes/virología , VIH-1/crecimiento & desarrollo , VIH-2/crecimiento & desarrollo , Humanos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Polisacáridos/aislamiento & purificación , Polisacáridos/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Virus de la Inmunodeficiencia de los Simios/crecimiento & desarrollo
14.
J Interferon Cytokine Res ; 16(12): 989-94, 1996 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-8973999

RESUMEN

As a pregnancy recognition signal, sheep trophoblast cells secrete a type I interferon, ovine interferon-tau (OvIFN-tau), which has potent antiviral activity. We studied the effects of a recombinant protein (rOv-IFN-tau) on the replication of ovine lentivirus (OvLV) in goat synovial membrane cells. The amount of provirus DNA, as measured by polymerase chain reaction (PCR), the virus titers, and the number of OvLV-induced syncytia were 76.5%, 82%, and 95%, respectively, lower in cultures treated with rOv-IFN-tau than in placebo-treated controls (p < 0.01). rOv-IFN-tau also reduced OvLV reverse transcriptase activity and protected cells from OvLV-induced cell lysis, but the effect was less dramatic. The antiviral activity increased with the concentration up to a maximum with 256 antiviral units of rOv-IFN-tau per ml.


Asunto(s)
Antivirales/farmacología , Interferón Tipo I , Interferón gamma/farmacología , Lentivirus/efectos de los fármacos , Proteínas Gestacionales/farmacología , Membrana Sinovial/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Animales , Células Cultivadas , Evaluación Preclínica de Medicamentos , Femenino , Células Gigantes/citología , Células Gigantes/efectos de los fármacos , Células Gigantes/virología , Lentivirus/aislamiento & purificación , Lentivirus/fisiología , Reacción en Cadena de la Polimerasa , Embarazo , Proteínas Recombinantes/farmacología , Ovinos , Membrana Sinovial/citología , Membrana Sinovial/virología
15.
Antiviral Res ; 25(2): 133-46, 1994 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-7847875

RESUMEN

A major disadvantage of conventional phototherapy is the requirement for the in situ delivery of stimulating photoenergy subsequent to the binding of photochemicals to target malignant cells, or virus-infected cells, or viruses. This drawback has resulted in considerable limitation in the use of photochemicals in photomedicine. To circumvent this problem, we have investigated the antiviral efficacy of a brominated 1,8-naphthalimide photocompound, termed LY66Br [3-bromo-4-(hexylamino)-N-hexyl-1,8-naphthalimide], which upon exposure to visible light at 420 nm generates independently of oxygen one or more stable antiviral molecular photoproducts (e.g., is 'preactivated'). Human cell lines infected with the human immunodeficiency virus type 1 (HIV-1), or with the human T-lymphotropic virus type-1 (HTLV-I) exposed to photochemical products of LY66Br (P-LY66Br) completely lost their ability to form syncytia in vitro. Photoproducts of P-LY66Br retain full antiviral activity for at least 3 and 6 weeks when stored at room temperature and at -80 degrees C, respectively. Concentrations of P-LY66Br, effective in inhibiting syncytium formation mediated by HIV-1 and HTLV-I, were nontoxic to normal red cell components of whole blood (red blood cell 2,3-diphosphoglyceric acid, adenosine triphosphate, osmotic fragility or blood type antigens). Additionally, no evidence of acute toxicity was demonstrated in mice following an intravenous bolus inoculation to achieve plasma concentration of 600 microM of P-LY66Br. These findings represent the first demonstration of inhibition of retrovirus-induced syncytium formation by a photochemical product, and justify further investigation of the preactivation process of photochemicals in the treatment of systemic viral infections such as the acquired immunodeficiency syndrome (AIDS), in cancer therapy, and in sterilization of banked blood products.


Asunto(s)
1-Naftilamina/análogos & derivados , Antivirales/farmacología , Efecto Citopatogénico Viral/efectos de los fármacos , Células Gigantes/efectos de los fármacos , VIH-1/efectos de los fármacos , Virus Linfotrópico T Tipo 1 Humano/efectos de los fármacos , 1-Naftilamina/síntesis química , 1-Naftilamina/farmacología , 1-Naftilamina/efectos de la radiación , 1-Naftilamina/toxicidad , Animales , Antivirales/síntesis química , Antivirales/efectos de la radiación , Antivirales/toxicidad , Eritrocitos/efectos de los fármacos , Femenino , Células Gigantes/virología , VIH-1/fisiología , Virus Linfotrópico T Tipo 1 Humano/fisiología , Masculino , Ratones , Ratones Endogámicos BALB C , Naftalimidas , Fotoquímica
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