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1.
Chem Pharm Bull (Tokyo) ; 67(7): 654-665, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257321

RESUMO

Quassinoids, one kind of triterpenoids with multiple bioactivities such as anti-cancer, anti-malarial, anti-oxidative, anti-microbial, anti-diabetic, anti-viral, and anti-inflammatory effects, have drawn much attention in recent years. Between 2004 and 2018, the structural characteristics and plant sources of 190 quassinoids were reported. Herein, the structure-activity relationships (SARs) of quassinoids along with the anti-cancer mechanisms of four representative quassinoids, eurycomanone, bruceine D, dehydrobruceine B, and brusatol are discussed. This review might be useful for further research and development of quassinoids.


Assuntos
Antineoplásicos Fitogênicos/química , Quassinas/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Antiprotozoários/química , Antiprotozoários/isolamento & purificação , Antiprotozoários/farmacologia , Antivirais/química , Antivirais/isolamento & purificação , Antivirais/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Humanos , Plantas/química , Plantas/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Quassinas/isolamento & purificação , Quassinas/farmacologia , Relação Estrutura-Atividade , Vírus do Mosaico do Tabaco/efeitos dos fármacos
2.
Carbohydr Res ; 478: 18-24, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31048118

RESUMO

The brown seaweed Scytosiphon lomentaria produces moderate amounts of fucoidans. By cetrimide fractionation, typical heavily sulfated galactofucans are obtained, with no major signs of chemical heterogeneity, together with fractions with higher proportions of xylose, mannose and uronic acids. Anyway, fucose is the most important monosaccharide in most of the subfractions of the subsequent extracts. The fucan moieties appear to be mostly as 3-linked α-l-fucopyranosyl units, with several patterns of sulfate and branching. Galactose is mostly 6-linked, whereas mannose appears to be 2-linked, and xylose appears mostly as terminal stubs. Small amounts of 2-O-acetylated fucose units appear. A high and selective antiviral activity against HSV-1 and HSV-2 was determined for the galactofucan fractions whereas the uronofucoidans were inactive.


Assuntos
Antivirais/farmacologia , Fucose/farmacologia , Galactose/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Polissacarídeos/farmacologia , Antivirais/química , Antivirais/isolamento & purificação , Configuração de Carboidratos , Fucose/química , Fucose/isolamento & purificação , Galactose/química , Galactose/isolamento & purificação , Testes de Sensibilidade Microbiana , Feófitas/química , Polissacarídeos/química , Polissacarídeos/isolamento & purificação
3.
Chem Biodivers ; 16(7): e1900202, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115136

RESUMO

Asprellosides A-K, nine new ursane-type triterpenoid glycosides (1-9), and two new oleanane-type triterpenoid glycosides (10 and 11), including six rare sulfated triterpenoid glycosides, were isolated from the roots of Ilex asprella. Their structures were determined on the basis of comprehensive spectroscopic analysis and chemical methods. Among these compounds, asprelloside B (2) and asprelloside C (3) are the first examples of triterpenoid glycosides bearing a rare 3,4-O-disulfo-xylopyranosyl residue. All the saponins isolated showed no significant effects against respiratory syncytial virus (RSV) and lipopolysaccharide-induced nitric oxide production in Raw264.7 macrophages.


Assuntos
Antivirais/farmacologia , Glicosídeos/farmacologia , Ilex/química , Óxido Nítrico/antagonistas & inibidores , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Antivirais/química , Antivirais/isolamento & purificação , Glicosídeos/química , Glicosídeos/isolamento & purificação , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Testes de Sensibilidade Microbiana , Conformação Molecular , Óxido Nítrico/biossíntese , Raízes de Plantas/química , Células RAW 264.7 , Triterpenos/química , Triterpenos/isolamento & purificação
4.
Science ; 364(6438): 399-402, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31023926

RESUMO

The maintenance of terminally differentiated cells, especially hepatocytes, in vitro has proven challenging. Here we demonstrated the long-term in vitro maintenance of primary human hepatocytes (PHHs) by modulating cell signaling pathways with a combination of five chemicals (5C). 5C-cultured PHHs showed global gene expression profiles and hepatocyte-specific functions resembling those of freshly isolated counterparts. Furthermore, these cells efficiently recapitulated the entire course of hepatitis B virus (HBV) infection over 4 weeks with the production of infectious viral particles and formation of HBV covalently closed circular DNA. Our study demonstrates that, with a chemical approach, functional maintenance of PHHs supports long-term HBV infection in vitro, providing an efficient platform for investigating HBV cell biology and antiviral drug screening.


Assuntos
Vírus da Hepatite B/crescimento & desenvolvimento , Hepatócitos/fisiologia , Hepatócitos/virologia , Cultura Primária de Células/métodos , Cultura de Vírus/métodos , Antivirais/isolamento & purificação , Antivirais/farmacologia , DNA Circular/biossíntese , DNA Circular/isolamento & purificação , DNA Viral/biossíntese , DNA Viral/isolamento & purificação , Avaliação Pré-Clínica de Medicamentos , Vírus da Hepatite B/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Transcriptoma , Vírion/efeitos dos fármacos , Vírion/crescimento & desenvolvimento
5.
Fitoterapia ; 137: 104151, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30999024

RESUMO

The norbisabolane-type sesquiterpenoids bearing a spiroketal functionality have been found in Phyllanthus spp. and showed anti-HBV activities. As part of an ongoing effort to search for promising anti-HBV sesquiterpenes from Phyllanthus plants, we report four new norbisabolane-type sesquiterpenoids, phyacidusin A (1), phyacidusin B (2), phllanthacidoid A1 (3) and phllanthacidoid N1 (4), from stem of P. acidus collected in Xishuangbanna, Yunnan province, China. The absolute configuration of new compounds was established by coupling constants and ROESY correlations, as well as comparation of NMR data with those of known compounds. The absolute configuration of new compounds 1 and 2 was further confirmed by X-ray diffraction. Compound 2 showed effect to HBsAg with an IC50 value of 11.2 ±â€¯0.01 µM, while compound 3 inhibited HBeAg secretion with an IC50 value of 57.1 ±â€¯0.02 µM. The results enriched the diversity of anti-HBV norbisabolane sesquiterpenes.


Assuntos
Antivirais/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Phyllanthus/química , Sesquiterpenos/farmacologia , Antivirais/isolamento & purificação , China , Células Hep G2 , Humanos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Caules de Planta/química , Sesquiterpenos/isolamento & purificação
6.
Fitoterapia ; 135: 27-32, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30946944

RESUMO

Five new compounds, including one bisabolane-type sesquiterpenoids, namely aspergillusene D (1), two new xanthones (2 and 3), and two new catecholderivatives (4 and 5), together with fourteen known compounds (6-19), were isolated and identified from the fungus Aspergillus sydowiiSCSIO 41,301 from the sponge Phakellia fusca. Their structures and absolute configurations were determined by extensive spectroscopic analysis and electronic circular dichroism (ECD) calculations. Most of the isolated compounds (1-3, and 6-19) were evaluated for their antiviral, cytotoxic, and antibacterial activities. Among them, new compounds 2 and 3 displayed obvious selective inhibitory activities against two influenza A virus subtypes, including A/Puerto Rico/8/34 (H1N1) and A/FM-1/1/47 (H1N1), with IC50 values ranging from 2.17 ±â€¯1.39 to 4.70 ±â€¯1.11 µM.


Assuntos
Antibacterianos/farmacologia , Antivirais/farmacologia , Aspergillus/química , Policetídeos/farmacologia , Poríferos/microbiologia , Sesquiterpenos/farmacologia , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antivirais/química , Antivirais/isolamento & purificação , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Estrutura Molecular , Policetídeos/química , Policetídeos/isolamento & purificação , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação
7.
Biomed Pharmacother ; 112: 108741, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30970528

RESUMO

Seaweeds are excellent source of bioactive compounds and seaweed-derived polysaccharides have demonstrated an array of biological effects. Here, we investigated the effect of polysaccharide of Sargassum weizhouense (PSW) on the inflammatory response in porcine circovirus type 2 (PCV2) infected mice and the underlying mechanism was studied according to the histone acetylation. After PCV2 infection, the levels of TNF-α, IL-1ß, IL-6, IL-8, IL-10, MCP-1, COX-1, COX-2 and HAT in both serum and spleen were significantly increased (P <0.05). The mRNA expression of TNF-α, IL-6, IL-10 and NF-κB p65 were elevated in PCV2 infected mice (P <0.05). The HDAC content in both serum and spleen as well the mRNA expression of HDAC1 were greatly decreased (P <0.05). PSW treatment dramatically inhibited the secretions of inflammatory cytokines and HATs, reduced mRNA expression of TNF-α, IL-6, IL-10 and NF-κB p65, but promoted HDAC secretion and mRNA expression of HDAC1 in PCV2-infected mice. The acetylation of both H3 and H4 was significantly up-regulated in PCV2-infected mice, and strongly inhibited by PSW treatment (P <0.01). These results suggested that PCV2 mediate the equilibrium between HATs and HDACs, alternate the histone acetylation and thus DNA packaging, and then activate the transcription of inflammatory cytokines. PSW could inhibit the histone acetylation and the production of inflammatory cytokines, showing excellent potentials in improving the resistance of host against PCV2 infection.


Assuntos
Antivirais/uso terapêutico , Infecções por Circoviridae/tratamento farmacológico , Histonas/metabolismo , Polissacarídeos/uso terapêutico , Sargassum/química , Acetilação , Animais , Antivirais/isolamento & purificação , Infecções por Circoviridae/imunologia , Citocinas/sangue , Feminino , Histona Acetiltransferases/metabolismo , Histona Desacetilases/metabolismo , Inflamação , Masculino , Camundongos Endogâmicos , Polissacarídeos/isolamento & purificação , Baço/imunologia
8.
Mar Drugs ; 17(4)2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30978942

RESUMO

The emergence of antibiotic resistance and viruses with high epidemic potential made unexplored marine environments an appealing target source for new metabolites. Marine fungi represent one of the most suitable sources for the discovery of new compounds. Thus, the aim of this work was (i) to isolate and identify fungi associated with the Atlantic sponge Grantia compressa; (ii) to study the fungal metabolites by applying the OSMAC approach (one strain; many compounds); (iii) to test fungal compounds for their antimicrobial activities. Twenty-one fungal strains (17 taxa) were isolated from G. compressa. The OSMAC approach revealed an astonishing metabolic diversity in the marine fungus Eurotium chevalieri MUT 2316, from which 10 compounds were extracted, isolated, and characterized. All metabolites were tested against viruses and bacteria (reference and multidrug-resistant strains). Dihydroauroglaucin completely inhibited the replication of influenza A virus; as for herpes simplex virus 1, total inhibition of replication was observed for both physcion and neoechinulin D. Six out of 10 compounds were active against Gram-positive bacteria with isodihydroauroglaucin being the most promising compound (minimal inhibitory concentration (MIC) 4-64 µg/mL) with bactericidal activity. Overall, G. compressa proved to be an outstanding source of fungal diversity. Marine fungi were capable of producing different metabolites; in particular, the compounds isolated from E. chevalieri showed promising bioactivity against well-known and emerging pathogens.


Assuntos
Antibacterianos/farmacologia , Antivirais/farmacologia , Biotecnologia/métodos , Eurotium/metabolismo , Poríferos/microbiologia , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antivirais/química , Antivirais/isolamento & purificação , Organismos Aquáticos/genética , Organismos Aquáticos/isolamento & purificação , Organismos Aquáticos/metabolismo , Biodiversidade , Cercopithecus aethiops , Cães , Eurotium/genética , Eurotium/isolamento & purificação , Bactérias Gram-Positivas/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Vírus da Influenza A/efeitos dos fármacos , Células Madin Darby de Rim Canino , Testes de Sensibilidade Microbiana , Células Vero , Replicação Viral/efeitos dos fármacos
9.
Rev Med Virol ; 29(3): e2043, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30942528

RESUMO

The constant outbreak of diseases caused by viral infections has caused serious harm to human health all over the world. Although many antiviral drugs have been approved for clinical use during the past decade, important issues, such as unsatisfactory efficacy, toxicity, and high cost of drugs, remain unresolved. Glycans are major components of the surfaces of both host cells and most viruses and play critical roles in the steps of viral infection. Marine glycans have more structural diversities than those found in humans. Most importantly, low toxicity and low-cost marine glycans have demonstrated potent antiviral activities through multiple molecular mechanisms. As a result, a series of marine glycan-derived agents are undergoing preclinical and clinical trials. This review discusses the recent progress in research on the marine glycan-based antiviral agents in clinical trials, relating to their structural features and clinical applications. In addition, molecular mechanisms of marine glycans involved in viral infection and novel strategies used in glycan-based drug development are critically reviewed and discussed.


Assuntos
Antivirais/isolamento & purificação , Antivirais/uso terapêutico , Organismos Aquáticos/química , Polissacarídeos/isolamento & purificação , Polissacarídeos/uso terapêutico , Animais , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos
10.
Org Lett ; 21(9): 3286-3289, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31008606

RESUMO

Rhodatin (1), a meroterpenoid featuring a unique pentacyclic scaffold with both spiro and spiroketal centers, and five unusual acorane-type sesquiterpenoids, named rhodocoranes A-E (2-6, respectively), are the first natural products isolated from the basidiomycete Rhodotus palmatus. Their structures were elucidated by two-dimensional NMR experiments and HRESIMS, while the absolute configuration of the substance family was determined by Mosher's method utilizing 2. Rhodatin strongly inhibited hepatitis C virus, whereas 4 displayed cytotoxicity and selective antifungal activity.


Assuntos
Antivirais/isolamento & purificação , Basidiomycota/química , Terpenos/isolamento & purificação , Antivirais/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Humanos , Estrutura Molecular , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Terpenos/farmacologia
11.
Mar Drugs ; 17(3)2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30836593

RESUMO

Ecklonia cava is edible seaweed that is found in Asian countries, such as Japan and Korea; and, its major components include fucoidan and phlorotannins. Phlorotannins that are isolated from E. cava are well-known to have an antioxidant effect and strong antiviral activity against porcine epidemic diarrhea virus (PEDV), which has a high mortality rate in piglets. In this study, the bioactive components were determined based on two different approaches: (i) bio-guided isolation using the antiviral activity against the H1N1 viral strain, which is a representative influenza virus that originates from swine and (ii) high-resolution mass spectrometry-based dereplication, including relative mass defects (RMDs) and HPLC-qTOFMS fragmentation analysis. The EC70 fraction showed the strongest antiviral activity and contained thirteen phlorotannins, which were predicted by dereplication. Ten compounds were directly isolated from E. cava extract and then identified. Moreover, the dereplication method allowed for the discovery of two new phlorotannins. The structures of these two isolated compounds were elucidated using NMR techniques and HPLC-qTOFMS fragmentation analysis. In addition, molecular modelling was applied to determine the absolute configurations of the two new compounds. The antiviral activities of seven major phlorotannins in active fraction were evaluated against two influenza A viral strains (H1N1 and H9N2). Six of the compounds showed moderate to strong effects on both of the viruses and phlorofucofuroeckol A (12), which showed an EC50 value of 13.48 ± 1.93 µM, is a potential active antiviral component of E. cava.


Assuntos
Antivirais/farmacologia , Produtos Biológicos/farmacologia , Feófitas/química , Alga Marinha/química , Taninos/farmacologia , Antivirais/química , Antivirais/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Cromatografia Líquida de Alta Pressão/métodos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H9N2/efeitos dos fármacos , Espectrometria de Massas em Tandem/métodos , Taninos/química , Taninos/isolamento & purificação
12.
Curr Pharm Biotechnol ; 20(3): 215-221, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30848197

RESUMO

BACKGROUND: Herpes simplex virus (HSV) and poliovirus (PV) are both agents of major concern in the public health system. It has been shown that Dimorphandra gardneriana galactomannans can be used as solubilizer vehicles in the manufacturing of medicine. Mangiferin is the major constituent of Mangifera indica and presents multiple medicinal and biological activities. OBJECTIVE: This study assayed the effect of D. gardneriana galactomannan combined with mangiferin (DgGmM) against HSV-1 and PV-1. METHODS: The DgGmM cytotoxicity was evaluated by the colorimetric MTT method and the antiviral activity by plaque reduction assay, immunofluorescence and polymerase chain reaction (PCR), in HEp-2 cells. RESULTS: The DgGmM showed a 50% cytotoxic concentration (CC50) > 2000 µg/mL. The 50% inhibitory concentrations (IC50) for HSV-1 and PV-1 were, respectively, 287.5 µg/mL and 206.2 µg/mL, with selectivity indexes (SI) > 6.95 for the former and > 9.69 for the latter. The DgGmM time-ofaddition protocol for HSV-1 showed a maximum inhibition at 500 µg/mL, when added concomitantly to infection and at the time 1 h post-infection (pi). While for PV-1, for the same protocol, the greatest inhibition, was also observed concomitantly to infection at 500 µg/mL and at the times 4 h and 8 h pi. The inhibition was also demonstrated by the decrease of fluorescent cells and/or the inhibition of specific viral genome. CONCLUSION: These results suggested that the DgGmM inhibited HSV-1 and PV-1 replication, with low cytotoxicity and high selectivity and, therefore, represents a potential candidate for further studies on the control of herpes and polio infections.


Assuntos
Antivirais/administração & dosagem , Herpesvirus Humano 1/efeitos dos fármacos , Mananas/administração & dosagem , Extratos Vegetais/administração & dosagem , Xantonas/administração & dosagem , Antivirais/isolamento & purificação , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Células Hep G2 , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1/fisiologia , Humanos , Mananas/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Poliovirus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Replicação Viral/fisiologia , Xantonas/isolamento & purificação
13.
J Ethnopharmacol ; 236: 124-128, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30853644

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Enterovirus 71 (EV71) has a propensity to cause hand-foot-and-mouth disease (HFMD) epidemics associated with neurological sequelae. Unfortunately, no drugs are currently available for the clinical treatment of EV71 infections. Sophoridine (SRI) is one of the most abundant alkaloids in Sophora flavescens Aiton (Leguminosae), which has been used to treat fever, throat inflammation, cancer, and other diseases. MATERIALS AND METHODS: In this study, we found that SRI inhibits EV71 infection in Vero cells. To study the antiviral activity of SRI, Vero cells were divided into 3 treatment groups based on the timing of SRI dosing: prior to viral adsorption (Group A), during viral adsorption (Group B), and after viral adsorption (Group C). We further revealed the antiviral activity of SRI with the attachment assay and the penetration assay. For Group A, 50% viability of Vero cells was observed at a SRI concentration of 61.39 µg/mL, whereas for Groups B, 50% viability was observed at SRI concentrations of 196.86 µg/mL. Furthermore, 29.7% cell viability was observed even at a SRI concentration of 1000 µg/mL in Groups C. The results show that SRI was highly effective against EV71 when Vero cells were pretreated with SRI for 2 h (Group A). Further researches indicate SRI was highly effective at inhibiting EV71 attachment when the SRI concentrations over 250 µg/mL (P < 0.001). CONCLUSIONS: We have shown that Vero cell viability increases when SRI is administered prior to viral adsorption. This suggests that SRI has the considerable potential as an antiviral for EV71 disease prevention.


Assuntos
Alcaloides/farmacologia , Antivirais/farmacologia , Enterovirus Humano A/efeitos dos fármacos , Quinolizinas/farmacologia , Alcaloides/isolamento & purificação , Animais , Antivirais/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Cercopithecus aethiops , Efeito Citopatogênico Viral/efeitos dos fármacos , Relação Dose-Resposta a Droga , Quinolizinas/isolamento & purificação , Sophora/química , Células Vero
14.
Vet Microbiol ; 230: 110-116, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30827375

RESUMO

Rift Valley fever virus (RVFV) is the causative agent of Rift Valley fever (RVF) that affects both livestock and humans. There are neither fully licensed RVF vaccines available for human or animal use, nor effective antiviral drugs approved for human use in the U.S. To identify antiviral compounds effective for RVF, we developed and employed a cell-based high-throughput assay using a recombinant RVFV MP-12 strain, which expresses Renilla luciferase in place of the NSs protein, to screen 727 small compounds purchased from the National Institutes of Health. Twenty-three compounds were initially identified using the screening assay. Two compounds, 6-azauridine and mitoxantrone, also inhibited the replication of the parental MP-12 strain encoding the NSs gene, with limited cytotoxic effects. The respective 50% inhibitory concentrations were 29.07 µM and 79.85 µM when tested with the parental MP-12 strain at a multiplicity of infection of 2. The compounds were further evaluated using the STAT-1 KO mouse model. At one hour post intranasal inoculation of MP-12 strain, mice were intranasally treated with each indicated compound twice daily. Mice treated with either placebo or 6-azauridine displayed severe weight loss and reached the threshold for euthanasia with obvious neurologic symptoms. Onset of disease was, however, delayed in mice treated with either ribavirin or mitoxantrone. The results indicated that mitoxantrone can reduce the severity of diseases in RVFV-infected mice. Our studies build the foundation for the initial screening and efficacy studies of RVF antivirals in a BSL-2 environment, avoiding the higher risks of BSL-3 exposure with wild-type virus.


Assuntos
Antivirais/farmacologia , Febre do Vale de Rift/tratamento farmacológico , Vírus da Febre do Vale do Rift/efeitos dos fármacos , Animais , Antivirais/isolamento & purificação , Azauridina/farmacologia , Linhagem Celular , Modelos Animais de Doenças , Descoberta de Drogas , Feminino , Ensaios de Triagem em Larga Escala , Concentração Inibidora 50 , Camundongos , Mitoxantrona/farmacologia , Vírus da Febre do Vale do Rift/fisiologia , Bibliotecas de Moléculas Pequenas/farmacologia , Replicação Viral/efeitos dos fármacos
15.
Viruses ; 11(2)2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30791582

RESUMO

Viral gastroenteritis is an important cause of morbidity and mortality worldwide, being particularly severe for children under the age of five. The most common viral agents of gastroenteritis are noroviruses, rotaviruses, sapoviruses, astroviruses and adenoviruses, however, no specific antiviral treatment exists today against any of these pathogens. We here discuss the feasibility of developing a broad-spectrum antiviral treatment against these diarrhea-causing viruses. This review focuses on the viral polymerase as an antiviral target, as this is the most conserved viral protein among the diverse viral families to which these viruses belong to. We describe the functional and structural similarities of the different viral polymerases, the antiviral effect of reported polymerase inhibitors and highlight common features that might be exploited in an attempt of designing such pan-polymerase inhibitor.


Assuntos
Antivirais/isolamento & purificação , Diarreia/tratamento farmacológico , Diarreia/virologia , Gastroenterite/tratamento farmacológico , Gastroenterite/virologia , RNA Replicase/metabolismo , Infecções por Adenovirus Humanos/tratamento farmacológico , Animais , Antivirais/uso terapêutico , Vírus de DNA/efeitos dos fármacos , Vírus de DNA/enzimologia , Humanos , Norovirus/efeitos dos fármacos , Norovirus/enzimologia , Inibidores da Síntese de Ácido Nucleico/isolamento & purificação , Inibidores da Síntese de Ácido Nucleico/uso terapêutico , Vírus de RNA/efeitos dos fármacos , Vírus de RNA/enzimologia , Rotavirus/efeitos dos fármacos , Rotavirus/enzimologia , Infecções por Rotavirus/tratamento farmacológico
16.
Viruses ; 11(2)2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30791609

RESUMO

Viruses are a major threat to human health and economic well-being. In recent years Ebola, Zika, influenza, and chikungunya virus epidemics have raised awareness that infections can spread rapidly before vaccines or specific antagonists can be made available. Broad-spectrum antivirals are drugs with the potential to inhibit infection by viruses from different groups or families, which may be deployed during outbreaks when specific diagnostics, vaccines or directly acting antivirals are not available. While pathogen-directed approaches are generally effective against a few closely related viruses, targeting cellular pathways used by multiple viral agents can have broad-spectrum efficacy. Virus entry, particularly clathrin-mediated endocytosis, constitutes an attractive target as it is used by many viruses. Using a phenotypic screening strategy where the inhibitory activity of small molecules was sequentially tested against different viruses, we identified 12 compounds with broad-spectrum activity, and found a subset blocking viral internalisation and/or fusion. Importantly, we show that compounds identified with this approach can reduce viral replication in a mouse model of Zika infection. This work provides proof of concept that it is possible to identify broad-spectrum inhibitors by iterative phenotypic screenings, and that inhibition of host-pathways critical for viral life cycles can be an effective antiviral strategy.


Assuntos
Antivirais/isolamento & purificação , Antivirais/farmacologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas , Internalização do Vírus/efeitos dos fármacos , Vírus/efeitos dos fármacos , Animais , Células HeLa , Humanos , Concentração Inibidora 50 , Camundongos , RNA Viral/genética , Replicação Viral/efeitos dos fármacos , Zika virus/efeitos dos fármacos , Infecção por Zika virus/tratamento farmacológico
17.
Fitoterapia ; 134: 101-107, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30794917

RESUMO

Four new bis-iridoid glycosides, saungmaygaosides A-D (1-4), and six known iridoid glycosides (5-10) were isolated from the n-butanol extract of the stems of Picrorhiza kurroa collected in Myanmar. Their structures were elucidated by extensive spectroscopic techniques. All of the isolates were assayed for anti-Vpr activity, using TREx-HeLa-Vpr cells. Among the isolates, saungmaygaoside D (4), sylvestroside IV dimethyl acetal (7), and sweroside (8) were the most potent inhibitors with effective doses of 5 and 10 µM, respectively, without showing any notable cytotoxicities.


Assuntos
Antivirais/farmacologia , Produtos do Gene vpr/antagonistas & inibidores , Glicosídeos Iridoides/farmacologia , Picrorhiza/química , Antivirais/isolamento & purificação , Células HeLa , Humanos , Glicosídeos Iridoides/isolamento & purificação , Estrutura Molecular , Mianmar , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Caules de Planta/química
18.
Antivir Chem Chemother ; 27: 2040206619830197, 2019 Jan-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30759993

RESUMO

Human metapneumovirus, a paramyxovirus discovered in 2001, is a major cause of lower respiratory infection in adults and children worldwide. There are no licensed vaccines or drugs for human metapneumovirus. We developed a fluorescent, cell-based medium-throughput screening assay for human metapneumovirus that captures inhibitors of all stages of the viral lifecycle except budding of progeny virus particles from the cell membrane. We optimized and validated the assay and performed a successful medium-throughput screening. A number of hits were identified, several of which were confirmed to inhibit viral replication in secondary assays. This assay offers potential to discover new antivirals for human metapneumovirus and related respiratory viruses. Compounds discovered using the medium-throughput screening may also provide useful probes of viral biology.


Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos/métodos , Metapneumovirus/efeitos dos fármacos , Animais , Antivirais/isolamento & purificação , Linhagem Celular , Humanos , Metapneumovirus/patogenicidade , Metapneumovirus/fisiologia , Testes de Sensibilidade Microbiana , Infecções Respiratórias/microbiologia , Inoculações Seriadas , Replicação Viral/efeitos dos fármacos
19.
Rev Med Virol ; 29(3): e2039, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30746831

RESUMO

The order of Bunyavirales includes numerous (re)emerging viruses that collectively have a major impact on human and animal health worldwide. There are no vaccines for human use or antiviral drugs available to prevent or treat infections with any of these viruses. The development of efficacious and safe drugs and vaccines is a pressing matter. Ideally, such antivirals possess pan-bunyavirus antiviral activity, allowing the containment of every bunya-related threat. The fact that many bunyaviruses need to be handled in laboratories with biosafety level 3 or 4, the great variety of species and the frequent emergence of novel species complicate such efforts. We here examined the potential druggable targets of bunyaviruses, together with the level of conservation of their biological functions, structure, and genetic similarity by means of heatmap analysis. In the light of this, we revised the available models and tools currently available, pointing out directions for antiviral drug discovery.


Assuntos
Antivirais/isolamento & purificação , Antivirais/farmacologia , Bunyaviridae/fisiologia , Bunyaviridae/ultraestrutura , Vacinas Virais/imunologia , Vacinas Virais/isolamento & purificação , Antivirais/uso terapêutico , Bunyaviridae/efeitos dos fármacos , Bunyaviridae/imunologia , Humanos
20.
J Agric Food Chem ; 67(11): 3168-3178, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30799619

RESUMO

In this study we report a secretory protein that was purified from Serratia marcescens strain S3 isolated from soil from the tobacco rhizosphere. Subsequent mass spectrometry and annotation characterized the protein as secretory alkaline metalloprotease (SAMP). SAMP plays a crucial role in inhibiting Tobacco mosaic virus (TMV). Transmission electron microscopy (TEM), dynamic light scattering (DLS), confocal microscopy, and microscale thermophoresis (MST) were employed to investigate the anti-TMV mechanism of SAMP. Our results demonstrated that SAMP, as a hydrolytic metal protease, combined and hydrolyzed TMV coat proteins to destroy the virus particles. This study is the first to investigate the antiviral effects of a S. marcescens metalloprotease, and our finding suggests that S. marcescens-S3 may be agronomically useful as a disease-controlling factor active against Tobacco mosaic virus.


Assuntos
Antivirais/farmacologia , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/farmacologia , Metaloproteases/farmacologia , Serratia marcescens/enzimologia , Antivirais/isolamento & purificação , Antivirais/metabolismo , Proteínas de Bactérias/isolamento & purificação , Metaloproteases/isolamento & purificação , Metaloproteases/metabolismo , Serratia marcescens/química , Serratia marcescens/genética , Vírus do Mosaico do Tabaco/efeitos dos fármacos , Vírus do Mosaico do Tabaco/crescimento & desenvolvimento
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